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Yan B, Fritsche AK, Haußner E, Inamdar TV, Laumen H, Boettcher M, Gericke M, Michl P, Rosendahl J. From Genes to Environment: Elucidating Pancreatic Carcinogenesis Through Genetically Engineered and Risk Factor-Integrated Mouse Models. Cancers (Basel) 2025; 17:1676. [PMID: 40427173 DOI: 10.3390/cancers17101676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/07/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically engineered mouse models (GEMMs). GEMMs, primarily driven by oncogenic Kras mutations and tumor suppressor gene alterations, offer a realistic platform for investigating pancreatic cancer initiation, progression, and metastasis. The incorporation of inducible somatic mutations and CRISPR-Cas9 screening methods has expanded their utility. To better recapitulate tumor initiation triggered by inflammatory cues, common pancreatic risk factors are being integrated into model designs. This approach aims to decipher the role of environmental factors as secondary or parallel triggers of tumor initiation alongside oncogenic burdens. Emerging models exploring pancreatitis, obesity, diabetes, and other risk factors offer significant translational potential. This review describes current mouse models for studying pancreatic carcinogenesis, their combination with inflammatory factors, and their utility in evaluating pathogenesis, providing guidance for selecting the most suitable models for pancreatic cancer research.
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Affiliation(s)
- Bin Yan
- Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Anne-Kristin Fritsche
- Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
- Institute of Anatomy, Leipzig University, 04103 Leipzig, Germany
| | - Erik Haußner
- Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Tanvi Vikrant Inamdar
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Helmut Laumen
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Michael Boettcher
- Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
| | - Martin Gericke
- Institute of Anatomy, Leipzig University, 04103 Leipzig, Germany
| | - Patrick Michl
- Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
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Li Z, Xing J. Role of sirtuins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic potential. Int J Biol Macromol 2025; 310:143591. [PMID: 40300682 DOI: 10.1016/j.ijbiomac.2025.143591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/22/2025] [Accepted: 04/26/2025] [Indexed: 05/01/2025]
Abstract
The high incidence and mortality rate of cardiac arrest (CA) establishes it as a critical clinical challenge in emergency medicine globally. Despite continuous advances in advanced life support (ALS) technology, the prognosis for patients experiencing cardiac arrest remains poor, with cerebral ischemia and reperfusion injury (CIRI) being a significant determinant of adverse neurological outcomes and increased mortality. Sirtuins (SIRTs) are a class of highly evolutionarily conserved NAD+-dependent histone deacylenzymes capable of regulating the expression of various cytoprotective genes to play a neuroprotective role in CIRI. SIRTs mainly regulate the levels of downstream proteins such as PGC 1-α, Nrf 2, NLRP 3, FoxOs, and PINK 1 to inhibit inflammatory response, attenuate oxidative stress, improve mitochondrial dysfunction, promote angiogenesis, and inhibit apoptosis while reducing CIRI. Natural active ingredients are widely used in regulating the protein level of SIRTs in the body because of their multi-components, multi-pathway, multi-target, and minimal toxic side effects. However, these naturally active ingredients still face many challenges related to drug targeting, pharmacokinetic properties, and drug delivery. The emergence and vigorous development of new drug delivery systems, such as nanoparticles, micromilk, and exosomes, provide strong support for solving the above problems. In the context of the rapid development of molecular biology technology, non-coding RNA (NcRNA), represented by miRNA and LncRNA, offers great potential for achieving gene-level precision medicine. In the context of multidisciplinary integration, combining SIRTs proteins with biotechnology, omics technologies, artificial intelligence, and material science will strongly promote the deepening of their basic research and expand their clinical application. This review describes the major signaling pathways of targeting SIRTs to mitigate CIRI, as well as the current research status of Chinese and Western medicine and medical means for the intervention level of SIRTs. Meanwhile, the challenges and possible solutions in the clinical application of targeted drugs are summarized. In the context of medical and industrial crossover, the development direction of SIRTs in the future is discussed to provide valuable reference for basic medical researchers and clinicians to improve the clinical diagnosis and treatment effects of CIRI.
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Affiliation(s)
- Zheng Li
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Jihong Xing
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
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Pereyra-Vergara F, Olivares-Corichi IM, Luna-Arias JP, Méndez-Luna D, García-Sánchez JR. Epicatechin Decreases UCP2 Gene Expression in MDA-MB-231 Breast Cancer Cells by the Presence of a Regulatory Element in the Promoter. Int J Mol Sci 2025; 26:4102. [PMID: 40362341 PMCID: PMC12071687 DOI: 10.3390/ijms26094102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/17/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Uncoupling protein 2 (UCP2) plays an important role in normal cells because it mitigates the cytotoxic effect of reactive oxygen species (ROS). However, its overexpression in cancer cells is related to drug resistance and increased cell proliferation due to a decrease in ROS production. In this context, molecules that regulate or block UCP2 have potential as anticancer agents. (-)-Epicatechin, a flavonoid that inhibits cell proliferation, increases ROS, and induces apoptosis in cancerous cells, was evaluated for its effects on UCP2 gene expression. For this purpose, the real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were performed in MDA-MB-231 and MCF-10A cells to determine the effects of (-)-epicatechin on UCP2 expression. Furthermore, the impact of (-)-epicatechin on cell viability was also determined. To analyze the transcriptional regulation of the UCP2 gene by (-)-epicatechin, a 5'-region of the human UCP2 gene (-2093/+297) was amplified, sequenced, cloned, and inserted into a reporter plasmid. To analyze the promoter activity and regulatory motif involved in the effects of (-)-epicatechin, several deletions of the UCP2 promoter were generated and transfected into MDA-MB-231 and MCF-10A cells. An electrophoretic mobility shift assay (EMSA) was carried out to detect the interaction between DNA and proteins involved in the effect of (-)-epicatechin. The increased expression of the UCP2 gene in MDA-MB-231 cells was decreased by (-)-epicatechin, and the opposite effect was observed in MCF-10A cells. The promoter region of the human UCP2 gene (-2093/+297) showed activity, which was decreased by (-)-epicatechin. A sequence of 117 bp located at position -109 b to +8 b has a fragment of 90 bp that is related to the (-)-epicatechin effect. Bioinformatics analysis and EMSA of this sequence revealed the presence of a regulatory site for a protein with zinc fingers. The presence of a response element to (-)-epicatechin in the human UCP2 promoter revealed that the inhibition of this gene in MDA-MB-231 breast cancer cells occurred at the transcriptional level. In this study, we propose the mechanism of action of (-)-epicatechin that could aid in cancer treatment.
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Affiliation(s)
- Fernando Pereyra-Vergara
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México C.P. 11340, Mexico;
| | - Ivonne María Olivares-Corichi
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México C.P. 11340, Mexico;
| | - Juan Pedro Luna-Arias
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Ciudad de México C.P. 07360, Mexico;
| | - David Méndez-Luna
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Zacatenco, Av. Wilfrido Massieu 399, Col. Nueva Industrial Vallejo, Alcaldía Gustavo A. Madero, Ciudad de México C.P. 07738, Mexico;
| | - José Rubén García-Sánchez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México C.P. 11340, Mexico;
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Fang HY, Ji LM, Hong CH. An innovative glutamine metabolism-related gene signature for predicting prognosis and immune landscape in cervical cancer. Discov Oncol 2025; 16:368. [PMID: 40113615 PMCID: PMC11926318 DOI: 10.1007/s12672-025-02109-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Cervical cancer (CC) is a major global malignancy affecting women. However, the precise mechanisms underlying glutamine's role in CC remain inadequately understood. This study systematically assessed the survival outcomes, immune landscape, and drug sensitivity profiles with CC patients by analyzing genes associated with glutamine metabolism. METHODS Transcriptomic data for the samples were sourced from the TCGA, GTEx, and GEO databases. Prognostic genes were identified through univariate, multivariate, and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses. The predictive accuracy of the model was assessed through the analysis of receiver operating characteristic (ROC) curves. A comprehensive nomogram was developed and evaluated for accuracy using calibration and Decision Curve Analysis (DCA) curves. Kaplan-Meier (K-M) survival curves were employed to estimate overall survival. The relationship between risk scores and immune infiltration was analyzed through Single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. Functional enrichment analysis and the construction of miRNA and transcription factors networks were conducted to explore the potential molecular mechanisms of the signature genes. RESULTS This investigation identified four signature genes associated with glutamine metabolism, UCP2, LEPR, TFRC, and RNaseH2A. We successfully developed a prognostic model with strong predictive performance. In the training set, the AUC values for 1-, 3-, and 5-year survival were 0.702, 0.719, and 0.721, respectively. In the validation set, the AUC values for these time points were 0.715, 0.696, and 0.739, respectively. Patients categorized as low-risk had notably improved survival rates than those identified as high-risk (P < 0.05). Additionally, a nomogram that combines clinical data and risk scores offered improved clinical net benefits over a broad range of threshold probabilities. Functional enrichment analysis revealed that these signature genes are strongly linked to the regulation of the cell cycle and intracellular oxygen levels. Furthermore, the gene signature displayed a significant negative correlation with the infiltration levels of most immune cell types. CONCLUSION This novel signature demonstrates robust predictive capability for prognostic survival probabilities and immune infiltration in CC patients, providing a fresh perspective for advancing precision treatment strategies in CC.
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Affiliation(s)
- Hai-Ya Fang
- Department of Obstetrics and Gynecology, Jinhua Municipal Central Hospital, Jinhua, 321000, China
| | - Li-Mei Ji
- Department of Obstetrics and Gynecology, Jinhua Municipal Central Hospital, Jinhua, 321000, China
| | - Cui-Hua Hong
- Department of Obstetrics and Gynecology, Wenzhou Central Hospital, No.252 East Baili Road, Wenzhou, 325100, China.
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Pohl EE, Vazdar M, Kreiter J. Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA-cycling hypothesis and beyond. Protein Sci 2025; 34:e70047. [PMID: 39969060 PMCID: PMC11837047 DOI: 10.1002/pro.70047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 02/20/2025]
Abstract
The mitochondrial ADP/ATP carrier (AAC, ANT), a member of the SLC25 family of solute carriers, plays a critical role in transporting purine nucleotides (ATP and ADP) as well as protons across the inner mitochondrial membrane. However, the precise mechanism and physiological significance of proton transport by ADP/ATP carrier remain unclear. Notably, the presence of uncouplers-such as long-chain fatty acids (FA) or artificial compounds like dinitrophenol (DNP)-is essential for this process. We explore two potential mechanisms that describe ADP/ATP carrier as either (i) a proton carrier that functions in the presence of FA or DNP, or (ii) an anion transporter (FA- or DNP). In the latter case, the proton is translocated by the neutral form of FA, which carries it from the matrix to the intermembrane space (FA-cycling hypothesis). Our recent results support this hypothesis. We describe a four-step mechanism for the "sliding" of the FA anion from the matrix to the mitochondrial intermembrane space and discuss a possible generalization of this mechanism to other SLC25 carriers.
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Affiliation(s)
- Elena E. Pohl
- Physiology and Biophysics Unit, Department of Biological Sciences and PathobiologyUniversity of Veterinary MedicineViennaAustria
| | - Mario Vazdar
- Department of Mathematics, Informatics, and CyberneticsUniversity of Chemistry and TechnologyPragueCzech Republic
| | - Jürgen Kreiter
- Physiology and Biophysics Unit, Department of Biological Sciences and PathobiologyUniversity of Veterinary MedicineViennaAustria
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6
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Jiang X, Wang T, Zhao B, Sun H, Dong Y, Ma Y, Li Z, Wu Y, Wang K, Guan X, Long B, Qin L, Shi W, Shi L, He Q, Liu W, Li M, Xiao L, Zhou C, Sun H, Yang J, Guan J, Zhou H, Yu Z, Jiao Z. KRAS G12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC. Cell Rep Med 2025; 6:101966. [PMID: 39970873 PMCID: PMC11866490 DOI: 10.1016/j.xcrm.2025.101966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/04/2024] [Accepted: 01/16/2025] [Indexed: 02/21/2025]
Abstract
The KRASG12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRASG12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRASG12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRASG12D-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRASG12D-mutated PDAC.
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Affiliation(s)
- Xiangyan Jiang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Tao Wang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Bin Zhao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Haonan Sun
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Yuman Dong
- Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
| | - Yong Ma
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Zhigang Li
- The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Yuxia Wu
- The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Keshen Wang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Xiaoying Guan
- Department of Pathology, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Bo Long
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Long Qin
- Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Wengui Shi
- Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Lei Shi
- School of Public Health, Lanzhou University, Lanzhou 730000, China
| | - Qichen He
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Wenbo Liu
- The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Mingdou Li
- The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Lixia Xiao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China
| | - Chengliang Zhou
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
| | - Hui Sun
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Jing Yang
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Junhong Guan
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Huinian Zhou
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Zeyuan Yu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Zuoyi Jiao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China.
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Qiao C, Wang L, Huang C, Jia Q, Bao W, Guo P, Tan D, Chen Z, Shi C, Rao Z, Zhang R, Wei W, Wang Z. Engineered Bacteria Manipulate Cysteine Metabolism to Boost Ferroptosis-Based Pancreatic Ductal Adenocarcinoma Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2412982. [PMID: 39696900 DOI: 10.1002/adma.202412982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/18/2024] [Indexed: 12/20/2024]
Abstract
Cysteine metabolism is a key determinant of the defense against ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Blocking cysteine metabolism may trigger potent ferroptosis in PDAC cells by generating lipid peroxides during tumor metabolic processes. However, current methods to limit cysteine availability fall short, failing to efficiently block cysteine metabolism due to inadequate tumor targeting and compensatory cysteine sources. Inspired by sulfur-metabolizing bacteria, synthetic biology to develop an engineered bacterium capable of directly depleting cysteine to block its metabolism is used. Acting as a living drug, these engineered bacteria colonize the tumor and continuously produce engineered cyst(e)inase enzyme (CGL) under the stimulation of tumor hypoxia. The CGL exhausts the substrate cysteine, completely impeding cysteine metabolism. This process dismantles the ferroptosis defense system in PDAC cells, triggers potent ferroptosis, and achieves efficient treatment. The results demonstrate that engineered bacteria designed for cysteine metabolism modulation possess unparalleled advantages in efficacy, persistence, and precision in blocking cysteine metabolism, making them highly suitable for effective ferroptosis treatment of PDAC.
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Affiliation(s)
- Chaoqiang Qiao
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
- Guangzhou Institute of Technology, Xidian University, Guangzhou, 510555, P. R. China
| | - Lexuan Wang
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
| | - Chuting Huang
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
| | - Qian Jia
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
| | - Weier Bao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Peilin Guo
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Dengxu Tan
- Laboratory Animal Center, Air Force Medical University, Xi'an, 710032, P. R. China
| | - Zhuang Chen
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
| | - Changhong Shi
- Laboratory Animal Center, Air Force Medical University, Xi'an, 710032, P. R. China
| | - Zhiping Rao
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
| | - Ruili Zhang
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
| | - Wei Wei
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Zhongliang Wang
- Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China
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Nan D, Yao W, Huang L, Liu R, Chen X, Xia W, Sheng H, Zhang H, Liang X, Lu Y. Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets. Cell Commun Signal 2025; 23:45. [PMID: 39856712 PMCID: PMC11760113 DOI: 10.1186/s12964-024-02018-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells.Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches.Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.
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Affiliation(s)
- Ding Nan
- School of Clinical Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Weiping Yao
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Luanluan Huang
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Ruiqi Liu
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiaoyan Chen
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wenjie Xia
- Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Hailong Sheng
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Haibo Zhang
- School of Clinical Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
| | - Xiaodong Liang
- School of Clinical Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
| | - Yanwei Lu
- School of Clinical Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
- Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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9
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Ma Q, Zhang W, Wu K, Shi L. The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy. Mol Cancer 2025; 24:14. [PMID: 39806421 PMCID: PMC11727292 DOI: 10.1186/s12943-024-02218-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 12/25/2024] [Indexed: 01/16/2025] Open
Abstract
KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis of fatty acids and nucleotides. However, the beyond mechanisms of KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related metabolic alterations in cancer cells and explore the prevalence and significance of KRAS mutation in shaping the tumor microenvironment and influencing epigenetic modification via various molecular activities. Given that cancer cells rely on these metabolic changes to sustain cell growth and survival, targeting these processes may represent a promising therapeutic strategy for KRAS-driven cancers.
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Affiliation(s)
- Qinglong Ma
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Wenyang Zhang
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
- Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Lei Shi
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
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10
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Ahmed A, Iaconisi GN, Di Molfetta D, Coppola V, Caponio A, Singh A, Bibi A, Capobianco L, Palmieri L, Dolce V, Fiermonte G. The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives. Int J Mol Sci 2024; 26:92. [PMID: 39795950 PMCID: PMC11719790 DOI: 10.3390/ijms26010092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/23/2024] [Accepted: 12/23/2024] [Indexed: 01/30/2025] Open
Abstract
Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.
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Affiliation(s)
- Amer Ahmed
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; (A.A.); (D.D.M.); (A.C.); (A.S.); (L.P.)
| | - Giorgia Natalia Iaconisi
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (G.N.I.); (L.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; (A.A.); (D.D.M.); (A.C.); (A.S.); (L.P.)
| | - Vincenzo Coppola
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH 43210, USA;
| | - Antonello Caponio
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; (A.A.); (D.D.M.); (A.C.); (A.S.); (L.P.)
| | - Ansu Singh
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; (A.A.); (D.D.M.); (A.C.); (A.S.); (L.P.)
| | - Aasia Bibi
- Department of Translational Biomedicine and Neuroscience, University of Bari, 70125 Bari, Italy;
| | - Loredana Capobianco
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (G.N.I.); (L.C.)
| | - Luigi Palmieri
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; (A.A.); (D.D.M.); (A.C.); (A.S.); (L.P.)
| | - Vincenza Dolce
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Giuseppe Fiermonte
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; (A.A.); (D.D.M.); (A.C.); (A.S.); (L.P.)
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11
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Wang K, Zhang L, Deng B, Zhao K, Chen C, Wang W. Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology. Mol Med 2024; 30:259. [PMID: 39707176 DOI: 10.1186/s10020-024-01027-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
Pancreatic diseases pose considerable health challenges due to their complex etiology and limited therapeutic options. Mitochondrial uncoupling protein 2 (UCP2), highly expressed in pancreatic tissue, participates in numerous physiological processes and signaling pathways, indicating its potential relevance in these diseases. Despite this, UCP2's role in acute pancreatitis (AP) remains underexplored, and its functions in chronic pancreatitis (CP) and pancreatic steatosis are largely unknown. Additionally, the mechanisms connecting various pancreatic diseases are intricate and not yet fully elucidated. Given UCP2's diverse functionality, broad expression in pancreatic tissue, and the distinct pathophysiological features of pancreatic diseases, this review offers a comprehensive analysis of current findings on UCP2's involvement in these conditions. We discuss recent insights into UCP2's complex regulatory mechanisms, propose that UCP2 may serve as a central regulatory factor in pancreatic disease progression, and hypothesize that UCP2 dysfunction could significantly contribute to disease pathogenesis. Understanding UCP2's role and mechanisms in pancreatic diseases may pave the way for innovative therapeutic and diagnostic approaches.
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Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Beiying Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kailiang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
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12
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Wu R, Zhu H, He Q, Yuan T, Yang B. Metabolic reprogramming in KRAS-mutant cancers: Proven targetable vulnerabilities and potential therapeutic strategies. Drug Discov Today 2024; 29:104220. [PMID: 39481592 DOI: 10.1016/j.drudis.2024.104220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 10/16/2024] [Accepted: 10/24/2024] [Indexed: 11/02/2024]
Abstract
Kras (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered 'untargetable'. Although specific KRASG12C inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.
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Affiliation(s)
- Ruilin Wu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China.
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13
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Beikbaghban T, Proietti L, Ebner J, Sango R, Rattei T, Weichhart T, Grebien F, Sternberg F, Pohl EE. Differential regulation of mitochondrial uncoupling protein 2 in cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2024; 1865:149486. [PMID: 38986826 PMCID: PMC7617651 DOI: 10.1016/j.bbabio.2024.149486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 06/27/2024] [Indexed: 07/12/2024]
Abstract
The persistent growth of cancer cells is underscored by complex metabolic reprogramming, with mitochondria playing a key role in the transition to aerobic glycolysis and representing new therapeutic targets. Mitochondrial uncoupling protein 2 (UCP2) has attracted interest because of its abundance in rapidly proliferating cells, including cancer cells, and its involvement in cellular metabolism. However, the specific contributions of UCP2 to cancer biology remain poorly defined. Our investigation of UCP2 expression in various human and mouse cancer cell lines aimed to elucidate its links to metabolic states, proliferation, and adaptation to environmental stresses such as hypoxia and nutrient deprivation. We observed significant variability in UCP2 expression across cancer types, with no direct correlation to their metabolic activity or proliferation rates. UCP2 abundance was also differentially affected by nutrient availability in different cancer cells, but UCP2 was generally downregulated under hypoxia. These findings challenge the notion that UCP2 is a marker of malignant potential and suggest its more complex involvement in the metabolic landscape of cancer.
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Affiliation(s)
- Taraneh Beikbaghban
- Physiology and Biophysics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Ludovica Proietti
- Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria
| | - Jessica Ebner
- Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria
| | - Roko Sango
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria; Doctoral School in Microbiology and Environmental Science, University of Vienna, Vienna, Austria
| | - Thomas Rattei
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Austria
| | - Florian Grebien
- Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Felix Sternberg
- Physiology and Biophysics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria; Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Austria.
| | - Elena E Pohl
- Physiology and Biophysics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria.
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14
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Zhao Y, Qin C, Lin C, Li Z, Zhao B, Li T, Zhang X, Wang W. Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets. Biochim Biophys Acta Rev Cancer 2024; 1879:189183. [PMID: 39303859 DOI: 10.1016/j.bbcan.2024.189183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/23/2024] [Accepted: 09/13/2024] [Indexed: 09/22/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a digestive system malignancy characterized by challenging early detection, limited treatment alternatives, and generally poor prognosis. Although there have been significant advancements in immunotherapy for hematological malignancies and various solid tumors in recent decades, with impressive outcomes in recent preclinical and clinical trials, the effectiveness of these therapies in treating PDAC continues to be modest. The unique immunological microenvironment of PDAC, especially the abnormal distribution, complex composition, and variable activation states of tumor-infiltrating immune cells, greatly restricts the effectiveness of immunotherapy. Undoubtedly, integrating data from both preclinical models and human studies helps accelerate the identification of reliable molecules and pathways responsive to targeted biological therapies and immunotherapies, thereby continuously optimizing therapeutic combinations. In this review, we delve deeply into how PDAC cells regulate the immune microenvironment through complex signaling networks, affecting the quantity and functional status of immune cells to promote immune escape and tumor progression. Furthermore, we explore the multi-modal immunotherapeutic strategies currently under development, emphasizing the transformation of the immunosuppressive environment into an anti-tumor milieu by targeting specific molecular and cellular pathways, providing insights for the development of novel treatment strategies.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Chen Lin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Xiangyu Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
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15
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Chu T, Zhang R, Liu X, Lin L, Li Y, Niu Z, Quan H, Zhao Y, Li Y. Influence of recipient KRAS gene rs712 polymorphisms on the overall survival rate of hepatocellular carcinoma after hepatic transplantation. Clin Exp Med 2024; 24:246. [PMID: 39460812 PMCID: PMC11512907 DOI: 10.1007/s10238-024-01509-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Hepatocellular carcinoma (HCC) recurrence appears commonly after liver transplantation (LT), and it severely affected the long-term survival of patients. Previous studies have proved that Rap1A is involved in hepatocarcinogenesis and metastasis, and demonstrated the significant association between KRAS rs712 polymorphism and HCC. However, the relationship between KRAS rs712 polymorphism and HCC recurrence after LT remained unclear. A total of 93 HCC patients who underwent LT from March 2008 to Dec 2015 was analyzed. The genotypes of both donors and recipients had been confirmed as KRAS rs712. The independent risk factors that associated with HCC recurrence were investigated with univariate and multivariate logistic regression analysis. The recurrence-free (RFS) and overall survival (OS) were calculated with Cox regression analysis. The KRAS rs712 genotype frequencies were determined using the Χ2 test and the minor allele frequencies (MAFs) of KRAS rs712 genotypes were calculated by Hardy-Weinberg equilibrium. We found that the recipient KRAS rs712 polymorphism was significantly associated with HCC recurrence after LT. Moreover, the Milan criteria, microvascular invasion and recipient KRAS rs712 genotype were proved to be independent risk factors for HCC recurrence after LT. Patients with donor TG/TT genotypes had a significantly higher RFS and OS than TT genotype. The TNM stage, microvascular invasion, Milan criteria, treatment and recipient KRAS rs712 genotype were independent factors for the RFS of LT patients. Recipient KRAS rs712 polymorphism is associated with HCC recurrence after liver transplantation and plays as a promising bio-predictor of overall survival rate of HCC risks after hepatic transplantation.
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Affiliation(s)
- Tiancheng Chu
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- Songjiang District Health Commission of Shanghai, Shanghai, China
| | - Rulin Zhang
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaolei Liu
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Li Lin
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yanning Li
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ziguang Niu
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Heng Quan
- Songjiang District Health Commission of Shanghai, Shanghai, China
| | - Yingying Zhao
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Yaohua Li
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
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16
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Zang X, Lei K, Wang J, Gong R, Gao C, Jing Z, Song J, Ren H. Targeting aberrant amino acid metabolism for pancreatic cancer therapy: Opportunities for nanoparticles. CHEMICAL ENGINEERING JOURNAL 2024; 498:155071. [DOI: 10.1016/j.cej.2024.155071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Sun LL, He HY, Li W, Jin WL, Wei YJ. The solute carrier transporters (SLCs) family in nutrient metabolism and ferroptosis. Biomark Res 2024; 12:94. [PMID: 39218897 PMCID: PMC11367818 DOI: 10.1186/s40364-024-00645-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024] Open
Abstract
Ferroptosis is a novel form of programmed cell death caused by damage to lipid membranes due to the accumulation of lipid peroxides in response to various stimuli, such as high levels of iron, oxidative stress, metabolic disturbance, etc. Sugar, lipid, amino acid, and iron metabolism are crucial in regulating ferroptosis. The solute carrier transporters (SLCs) family, known as the "metabolic gating" of cells, is responsible for transporting intracellular nutrients and metabolites. Recent studies have highlighted the significant role of SLCs family members in ferroptosis by controlling the transport of various nutrients. Here, we summarized the function and mechanism of SLCs in ferroptosis regulated by ion, metabolic control of nutrients, and multiple signaling pathways, with a focus on SLC-related transporters that primarily transport five significant components: glucose, amino acid, lipid, trace metal ion, and other ion. Furthermore, the potential clinical applications of targeting SLCs with ferroptosis inducers for various diseases, including tumors, are discussed. Overall, this paper delves into the novel roles of the SLCs family in ferroptosis, aiming to enhance our understanding of the regulatory mechanisms of ferroptosis and identify new therapeutic targets for clinical applications.
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Affiliation(s)
- Li-Li Sun
- School of Life Science, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Hai-Yan He
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Wei Li
- Division of Hematology and Oncology, Department of Pediatrics, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Wei-Lin Jin
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, P. R. China.
| | - Yi-Ju Wei
- School of Life Science, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
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18
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Liu Y, Miao Z, Yang Q. AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation. Cell Biochem Biophys 2024; 82:2037-2053. [PMID: 38789662 DOI: 10.1007/s12013-024-01311-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2024] [Indexed: 05/26/2024]
Abstract
The dependence of hepatocellular carcinoma (HCC) cells on glutamine suggests the feasibility of targeting glutamine metabolism for therapy. However, drugs inhibiting glutamine uptake and breakdown have not shown promising outcomes. Therefore, investigating the mechanism of glutamine metabolism reprogramming in HCC cells is crucial. We used bioinformatics approaches to investigate the metabolic flux of glutamine in HCC cells and validated it using qRT-PCR and western blotting. HCC cells were cultured in glutamine-deprived medium, and changes in glutamate and ATP levels were monitored. Western blotting was employed to assess the expression of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and autophagy-related proteins. The impact of Solute carrier family 25 member 12 (AGC1) on HCC cell proliferation was studied using CCK-8 and colony formation assays. Furthermore, the effects of AGC1 knockdown via siRNA on metabolic reprogramming and energy supply during glutamine deprivation in HCC were explored. During glutamine deprivation, HCC cells sustain cytosolic asparagine synthesis and ATP production through AGC1. Low ATP levels activate AMPK and inhibit mTOR activation, inducing autophagy to rescue HCC cell survival. Knockdown of AGC1 inhibits mitochondrial aspartate output and continuously activates autophagy, rendering HCC cells more sensitive to glutamine deprivation. AGC1 serves as a critical node in the reprogramming of glutamine metabolism and energy supply in HCC cells. This study provides theoretical support for overcoming resistance to drugs targeting glutamine metabolism.
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Affiliation(s)
- Yan Liu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China
| | - Zeyu Miao
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China.
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19
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Wang Z, Liu M, Yang Q. Glutamine and leukemia research: progress and clinical prospects. Discov Oncol 2024; 15:391. [PMID: 39215845 PMCID: PMC11365919 DOI: 10.1007/s12672-024-01245-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Leukemia is an abnormal proliferation of white blood cells that occurs in bone marrow and expands through the blood. It arises from dysregulated differentiation, uncontrolled growth, and inhibition of apoptosis. Glutamine (GLN) is a "conditionally essential" amino acid that promotes growth and proliferation of leukemic cells. Recently, details about the role of GLN and its metabolism in the diagnosis and treatment of acute myeloid, chronic lymphocytic, and acute lymphoblastic leukemia have emerged. The uptake of GLN by leukemia cells and the dynamic changes of glutamine-related indexes in leukemia patients may be able to assist in determining whether the condition of leukemia is in a state of progression, remission or relapse. Utilizing the possible differences in GLN metabolism in different subtypes of leukemia may help to differentiate between different subtypes of leukemia, thus providing a basis for accurate diagnosis. Targeting GLN metabolism in leukemia requires simultaneous blockade of multiple metabolic pathways without interfering with the normal cellular and immune functions of the body to achieve effective leukemia therapy. The present review summarizes recent advances, possible applications, and clinical perspectives of GLN metabolism in leukemia. In particular, it focuses on the prospects of GLN metabolism in the diagnosis and treatment of acute myeloid leukemia. The review provides new directions and hints at potential roles for future clinical treatments and studies.
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Affiliation(s)
- Zexin Wang
- Mianyang Central Hospital, Fucheng District, Mianyang, 621000, Sichuan, China.
| | - Miao Liu
- Mianyang Central Hospital, Fucheng District, Mianyang, 621000, Sichuan, China
| | - Qiang Yang
- Mianyang Central Hospital, Fucheng District, Mianyang, 621000, Sichuan, China
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Marhl M. What do stimulated beta cells have in common with cancer cells? Biosystems 2024; 242:105257. [PMID: 38876357 DOI: 10.1016/j.biosystems.2024.105257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/11/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
This study investigates the metabolic parallels between stimulated pancreatic beta cells and cancer cells, focusing on glucose and glutamine metabolism. Addressing the significant public health challenges of Type 2 Diabetes (T2D) and cancer, we aim to deepen our understanding of the mechanisms driving insulin secretion and cellular proliferation. Our analysis of anaplerotic cycles and the role of NADPH in biosynthesis elucidates their vital functions in both processes. Additionally, we point out that both cell types share an antioxidative response mediated by the Nrf2 signaling pathway, glutathione synthesis, and UCP2 upregulation. Notably, UCP2 facilitates the transfer of C4 metabolites, enhancing reductive TCA cycle metabolism. Furthermore, we observe that hypoxic responses are transient in beta cells post-stimulation but persistent in cancer cells. By synthesizing these insights, the research may suggest novel therapeutic targets for T2D, highlighting the shared metabolic strategies of stimulated beta cells and cancer cells. This comparative analysis not only illuminates the metabolic complexity of these conditions but also emphasizes the crucial role of metabolic pathways in cell function and survival, offering fresh perspectives for tackling T2D and cancer challenges.
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Affiliation(s)
- Marko Marhl
- Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000, Maribor, Slovenia; Faculty of Education, University of Maribor, Koroška cesta 160, 2000, Maribor, Slovenia; Faculty of Natural Sciences and Mathematics, University of Maribor, Koroška cesta 160, 2000, Maribor, Slovenia.
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21
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Liu X, Ren B, Ren J, Gu M, You L, Zhao Y. The significant role of amino acid metabolic reprogramming in cancer. Cell Commun Signal 2024; 22:380. [PMID: 39069612 DOI: 10.1186/s12964-024-01760-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/21/2024] [Indexed: 07/30/2024] Open
Abstract
Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.
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Affiliation(s)
- Xiaohong Liu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R, 100023, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, P.R, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, 100023, P.R, China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R, 100023, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, P.R, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, 100023, P.R, China
| | - Jie Ren
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R, 100023, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, P.R, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, 100023, P.R, China
| | - Minzhi Gu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R, 100023, China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, P.R, China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, 100023, P.R, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R, 100023, China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, P.R, China.
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, 100023, P.R, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R, 100023, China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, P.R, China.
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, 100023, P.R, China.
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22
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Chen B, Lu M, Chen Q, Zou E, Bo Z, Li J, Zhao R, Zhao J, Yu Z, Chen G, Wu L. Systematic profiling of mitochondria-related transcriptome in tumorigenesis, prognosis, and tumor immune microenvironment of intrahepatic cholangiocarcinoma: a multi-center cohort study. Front Genet 2024; 15:1430885. [PMID: 39130746 PMCID: PMC11310173 DOI: 10.3389/fgene.2024.1430885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Background Mitochondrial dysfunction has been shown to play a critical role in cancer biology. However, its involvement in intrahepatic cholangiocarcinoma (iCCA) remains significantly understudied. Methods RNA sequencing data of 30 pairs of iCCA and paracancerous tissues were collected from the First Affiliated Hospital of Wenzhou Medical University (WMU). The WMU cohort (n = 30) was integrated with public TCGA (n = 30) and GSE107943 (n = 30) datasets to establish a multi-center iCCA cohort. We merged the TCGA and GSE107943 cohorts into an exploration cohort to develop a mitochondria signature for prognosis assessment, and utilized the WMU cohort for external validation. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Hallmarker analyses were used for functional interpretation of iCCA associated mitochondria-related genes (MRGs). In addition, unsupervised clustering was performed to identify mitochondria-based iCCA subtypes with the data of three institutions. Further investigations were conducted to examine the impact of mitochondrial dysfunction on drug responses, alteration of the tumor immune microenvironment, and immune responses. Results Two hundred and sixty-three iCCA-related MRGs were identified to be related to fatty acid metabolism, oxidative phosphorylation, and apoptosis. Through univariate and multivariate Cox, and LASSO analyses, a mitochondria signature with five optimal MRGs was established to evaluate the prognosis of iCCA patients with the AUC values ranged from 0.785 to 0.928 in the exploration cohort. The signature also exhibited satisfactory performance in the WMU cohort with AUC values of 0.817-0.871, and was identified as an independent risk predictor in both cohorts. Additionally, we found that patients with higher mitochondria score with poor prognosis presented lower infiltration levels of CD4+ T-cell, NK cells, and monocytes, and demonstrated higher sensitivity to targeted therapies, including sorafenib. Furthermore, two distant mitochondria-based subtypes were determined, and subtype 2 was associated with shorter survival time and immunosuppressive tumor microenvironment. Finally, the differential protein expression of five key MRGs was verified by Immunohistochemistry. Conclusion We found mitochondrial dysfunction modulates aberrant metabolism, oxidative stress, immune responses, apoptosis, and drug sensitivity in iCCA. A mitochondria signature and two mitochondria-based iCCA subtypes were identified for clinical risk stratification and immunophenotyping.
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Affiliation(s)
- Bo Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mengmeng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiwen Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Enguang Zou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiacheng Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rui Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jungang Zhao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhengping Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lijun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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23
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Fontes MG, Silva C, Roldán WH, Monteiro G. Exploring the potential of asparagine restriction in solid cancer treatment: recent discoveries, therapeutic implications, and challenges. Med Oncol 2024; 41:176. [PMID: 38879707 DOI: 10.1007/s12032-024-02424-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 06/07/2024] [Indexed: 06/25/2024]
Abstract
Asparagine is a non-essential amino acid crucial for protein biosynthesis and function, and therefore cell maintenance and growth. Furthermore, this amino acid has an important role in regulating several metabolic pathways, such as tricarboxylic acid cycle and the urea cycle. When compared to normal cells, tumor cells typically present a higher demand for asparagine, making it a compelling target for therapy. In this review article, we investigate different facets of asparagine bioavailability intricate role in malignant tumors raised from solid organs. We take a comprehensive look at asparagine synthetase expression and regulation in cancer, including the impact on tumor growth and metastasis. Moreover, we explore asparagine depletion through L-asparaginase as a potential therapeutic method for aggressive solid tumors, approaching different formulations of the enzyme and combinatory therapies. In summary, here we delve into studies about endogenous and exogenous asparagine availability in solid cancers, analyzing therapeutic implications and future challenges.
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Affiliation(s)
- Marina Gabriel Fontes
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil
| | - Carolina Silva
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil
| | - William Henry Roldán
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil
| | - Gisele Monteiro
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil.
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24
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Caggiano EG, Taniguchi CM. UCP2 and pancreatic cancer: conscious uncoupling for therapeutic effect. Cancer Metastasis Rev 2024; 43:777-794. [PMID: 38194152 PMCID: PMC11156755 DOI: 10.1007/s10555-023-10157-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/13/2023] [Indexed: 01/10/2024]
Abstract
Pancreatic cancer has an exaggerated dependence on mitochondrial metabolism, but methods to specifically target the mitochondria without off target effects in normal tissues that rely on these organelles is a significant challenge. The mitochondrial uncoupling protein 2 (UCP2) has potential as a cancer-specific drug target, and thus, we will review the known biology of UCP2 and discuss its potential role in the pathobiology and future therapy of pancreatic cancer.
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Affiliation(s)
- Emily G Caggiano
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Cullen M Taniguchi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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25
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Wen S, Lin X, Luo W, Pan Y, Liao F, Wang Z, Zhan B, Feng J, Huang H. Metabolic difference between patient-derived xenograft model of pancreatic ductal adenocarcinoma and corresponding primary tumor. BMC Cancer 2024; 24:485. [PMID: 38632504 PMCID: PMC11022326 DOI: 10.1186/s12885-024-12193-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 03/27/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Patients-derived xenograft (PDX) model have been widely used for tumor biological and pathological studies. However, the metabolic similarity of PDX tumor to the primary cancer (PC) is still unknown. METHODS In present study, we established PDX model by engrafting primary tumor of pancreatic ductal adenocarcinoma (PDAC), and then compared the tumor metabolomics of PC, the first generation of PDX tumor (PDXG1), and the third generation of PDX tumor (PDXG3) by using 1H NMR spectroscopy. Then, we assessed the differences in response to chemotherapy between PDXG1 and PDXG3 and corresponding metabolomic differences in drug-resistant tumor tissues. To evaluate the metabolomic similarity of PDX to PC, we also compared the metabolomic difference of cell-derived xenograft (CDX) vs. PC and PDX vs. PC. RESULTS After engraftment, PDXG1 tumor had a low level of lactate, pyruvate, citrate and multiple amino acids (AAs) compared with PC. Metabolite sets enrichment and metabolic pathway analyses implied that glycolysis metabolisms were suppressed in PDXG1 tumor, and tricarboxylic acid cycle (TCA)-associated anaplerosis pathways, such as amino acids metabolisms, were enhanced. Then, after multiple passages of PDX, the altered glycolysis and TCA-associated anaplerosis pathways were partially recovered. Although no significant difference was observed in the response of PDXG1 and PDXG3 to chemotherapy, the difference in glycolysis and amino acids metabolism between PDXG1 and PDXG3 could still be maintained. In addition, the metabolomic difference between PC and CDX models were much larger than that of PDX model and PC, indicating that PDX model still retain more metabolic characteristics of primary tumor which is more suitable for tumor-associated metabolism research. CONCLUSIONS Compared with primary tumor, PDX models have obvious difference in metabolomic level. These findings can help us design in vivo tumor metabolomics research legitimately and analyze the underlying mechanism of tumor metabolic biology thoughtfully.
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Affiliation(s)
- Shi Wen
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, 351001, Fuzhou, China
| | - Xianchao Lin
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, 351001, Fuzhou, China
| | - Wei Luo
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, 351001, Fuzhou, China
| | - Yu Pan
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, 351001, Fuzhou, China
| | - Fei Liao
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, 351001, Fuzhou, China
| | - Zhenzhao Wang
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, No. 422, Siming South Road, Siming District, 361005, Xiamen, China
| | - Bohan Zhan
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, No. 422, Siming South Road, Siming District, 361005, Xiamen, China
| | - Jianghua Feng
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, No. 422, Siming South Road, Siming District, 361005, Xiamen, China.
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, 351001, Fuzhou, China.
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26
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Ren J, Ren B, Liu X, Cui M, Fang Y, Wang X, Zhou F, Gu M, Xiao R, Bai J, You L, Zhao Y. Crosstalk between metabolic remodeling and epigenetic reprogramming: A new perspective on pancreatic cancer. Cancer Lett 2024; 587:216649. [PMID: 38311052 DOI: 10.1016/j.canlet.2024.216649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/21/2023] [Accepted: 01/13/2024] [Indexed: 02/06/2024]
Abstract
Pancreatic cancer is a highly malignant solid tumor with a poor prognosis and a high mortality rate. Thus, exploring the mechanisms underlying the development and progression of pancreatic cancer is critical for identifying targets for diagnosis and treatment. Two important hallmarks of cancer-metabolic remodeling and epigenetic reprogramming-are interconnected and closely linked to regulate one another, creating a complex interaction landscape that is implicated in tumorigenesis, invasive metastasis, and immune escape. For example, metabolites can be involved in the regulation of epigenetic enzymes as substrates or cofactors, and alterations in epigenetic modifications can in turn regulate the expression of metabolic enzymes. The crosstalk between metabolic remodeling and epigenetic reprogramming in pancreatic cancer has gained considerable attention. Here, we review the emerging data with a focus on the reciprocal regulation of metabolic remodeling and epigenetic reprogramming. We aim to highlight how these mechanisms could be applied to develop better therapeutic strategies.
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Affiliation(s)
- Jie Ren
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Xiaohong Liu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Ming Cui
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Yuan Fang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Xing Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Feihan Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Minzhi Gu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Ruiling Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Jialu Bai
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, PR China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, PR China; National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing 100023, PR China.
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27
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De Leonardis F, Ahmed A, Vozza A, Capobianco L, Riley CL, Barile SN, Di Molfetta D, Tiziani S, DiGiovanni J, Palmieri L, Dolce V, Fiermonte G. Human mitochondrial uncoupling protein 3 functions as a metabolite transporter. FEBS Lett 2024; 598:338-346. [PMID: 38058167 PMCID: PMC10922436 DOI: 10.1002/1873-3468.14784] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/08/2023]
Abstract
Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient 'uncoupled' respiration, including fasting and exercise. Here, we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, sulphate and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.
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Affiliation(s)
- Francesco De Leonardis
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Amer Ahmed
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Angelo Vozza
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Loredana Capobianco
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Christopher L. Riley
- Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Simona Nicole Barile
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Daria Di Molfetta
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Stefano Tiziani
- Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX. USA
| | - Luigi Palmieri
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Vincenza Dolce
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Giuseppe Fiermonte
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
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28
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Li X, Peng X, Li Y, Wei S, He G, Liu J, Li X, Yang S, Li D, Lin W, Fang J, Yang L, Li H. Glutamine addiction in tumor cell: oncogene regulation and clinical treatment. Cell Commun Signal 2024; 22:12. [PMID: 38172980 PMCID: PMC10763057 DOI: 10.1186/s12964-023-01449-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024] Open
Abstract
After undergoing metabolic reprogramming, tumor cells consume additional glutamine to produce amino acids, nucleotides, fatty acids, and other substances to facilitate their unlimited proliferation. As such, the metabolism of glutamine is intricately linked to the survival and progression of cancer cells. Consequently, targeting the glutamine metabolism presents a promising strategy to inhibit growth of tumor cell and cancer development. This review describes glutamine uptake, metabolism, and transport in tumor cells and its pivotal role in biosynthesis of amino acids, fatty acids, nucleotides, and more. Furthermore, we have also summarized the impact of oncogenes like C-MYC, KRAS, HIF, and p53 on the regulation of glutamine metabolism and the mechanisms through which glutamine triggers mTORC1 activation. In addition, role of different anti-cancer agents in targeting glutamine metabolism has been described and their prospective applications are assessed.
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Affiliation(s)
- Xian Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yan Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Dai Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Weikai Lin
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jianjun Fang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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Gao R, Zhou D, Qiu X, Zhang J, Luo D, Yang X, Qian C, Liu Z. Cancer Therapeutic Potential and Prognostic Value of the SLC25 Mitochondrial Carrier Family: A Review. Cancer Control 2024; 31:10732748241287905. [PMID: 39313442 PMCID: PMC11439189 DOI: 10.1177/10732748241287905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 09/25/2024] Open
Abstract
Transporters of the solute carrier family 25 (SLC25) regulate the intracellular distribution and concentration of nucleotides, amino acids, dicarboxylates, and vitamins within the mitochondrial and cytoplasmic matrices. This mechanism involves changes in mitochondrial function, regulation of cellular metabolism, and the ability to provide energy. In this review, important members of the SLC25 family and their pathways affecting tumorigenesis and progression are elucidated, highlighting the diversity and complexity of these pathways. Furthermore, the significant potential of the members of SLC25 as both cancer therapeutic targets and biomarkers will be emphasized.
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Affiliation(s)
- Renzhuo Gao
- School of Queen Mary, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Dan Zhou
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xingpeng Qiu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jiayi Zhang
- School of Queen Mary, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Daya Luo
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiaohong Yang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Caiyun Qian
- Department of Blood Transfusion, Key Laboratory of Jiangxi Province for Transfusion Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zhuoqi Liu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
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30
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Kreiter J, Tyschuk T, Pohl EE. Uncoupling Protein 3 Catalyzes the Exchange of C4 Metabolites Similar to UCP2. Biomolecules 2023; 14:21. [PMID: 38254621 PMCID: PMC10813146 DOI: 10.3390/biom14010021] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 01/24/2024] Open
Abstract
Uncoupling protein 3 (UCP3) belongs to the mitochondrial carrier protein superfamily SLC25 and is abundant in brown adipose tissue (BAT), the heart, and muscles. The expression of UCP3 in tissues mainly dependent on fatty acid oxidation suggests its involvement in cellular metabolism and has drawn attention to its possible transport function beyond the transport of protons in the presence of fatty acids. Based on the high homology between UCP2 and UCP3, we hypothesized that UCP3 transports C4 metabolites similar to UCP2. To test this, we measured the transport of substrates against phosphate (32Pi) in proteoliposomes reconstituted with recombinant murine UCP3 (mUCP3). We found that mUCP3 mainly transports aspartate and sulfate but also malate, malonate, oxaloacetate, and succinate. The transport rates calculated from the exchange of 32Pi against extraliposomal aspartate and sulfate were 23.9 ± 5.8 and 17.5 ± 5.1 µmol/min/mg, respectively. Using site-directed mutagenesis, we revealed that mutation of R84 resulted in impaired aspartate/phosphate exchange, demonstrating its critical role in substrate transport. The difference in substrate preference between mUCP2 and mUCP3 may be explained by their different tissue expression patterns and biological functions in these tissues.
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Affiliation(s)
| | | | - Elena E. Pohl
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, 1210 Vienna, Austria; (J.K.); (T.T.)
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31
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Negri A, Ward C, Bucci A, D'Angelo G, Cauchy P, Radesco A, Ventura AB, Walton DS, Clarke M, Mandriani B, Pappagallo SA, Mondelli P, Liao K, Gargano G, Zaccaria GM, Viggiano L, Lasorsa FM, Ahmed A, Di Molfetta D, Fiermonte G, Cives M, Guarini A, Vegliante MC, Ciavarella S, Frampton J, Volpe G. Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML. Cell Death Dis 2023; 14:763. [PMID: 37996430 PMCID: PMC10667525 DOI: 10.1038/s41419-023-06276-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/27/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023]
Abstract
The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.
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Affiliation(s)
- A Negri
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - C Ward
- Edge Impulse Inc., San Jose, CA, USA
| | - A Bucci
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - G D'Angelo
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - P Cauchy
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - A Radesco
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - A B Ventura
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - D S Walton
- Clent Life Sciences, DY84HD, Stourbridge, UK
| | - M Clarke
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, B152TT, Birmingham, UK
| | - B Mandriani
- Department of Bioscience, Biotechnology and Environment, University of Bari "Aldo Moro", 70125, Bari, Italy
| | - S A Pappagallo
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - P Mondelli
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - K Liao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China
| | - G Gargano
- Department of Mathematics, University of Bari "Aldo Moro", Bari, Italy
| | - G M Zaccaria
- Department of Electrical and Information Engineering, Polytechnic University of Bari, Bari, Italy
| | - L Viggiano
- Department of Biology, University of Bari "Aldo Moro", Bari, Italy
| | - F M Lasorsa
- Department of Bioscience, Biotechnology and Environment, University of Bari "Aldo Moro", 70125, Bari, Italy
| | - A Ahmed
- Department of Bioscience, Biotechnology and Environment, University of Bari "Aldo Moro", 70125, Bari, Italy
| | - D Di Molfetta
- Department of Bioscience, Biotechnology and Environment, University of Bari "Aldo Moro", 70125, Bari, Italy
| | - G Fiermonte
- Department of Bioscience, Biotechnology and Environment, University of Bari "Aldo Moro", 70125, Bari, Italy
| | - M Cives
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - A Guarini
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - M C Vegliante
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - S Ciavarella
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - J Frampton
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, B152TT, Birmingham, UK.
| | - G Volpe
- Hematology and Cell Therapy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.
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Shuvalov O, Kirdeeva Y, Daks A, Fedorova O, Parfenyev S, Simon HU, Barlev NA. Phytochemicals Target Multiple Metabolic Pathways in Cancer. Antioxidants (Basel) 2023; 12:2012. [PMID: 38001865 PMCID: PMC10669507 DOI: 10.3390/antiox12112012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Cancer metabolic reprogramming is a complex process that provides malignant cells with selective advantages to grow and propagate in the hostile environment created by the immune surveillance of the human organism. This process underpins cancer proliferation, invasion, antioxidant defense, and resistance to anticancer immunity and therapeutics. Perhaps not surprisingly, metabolic rewiring is considered to be one of the "Hallmarks of cancer". Notably, this process often comprises various complementary and overlapping pathways. Today, it is well known that highly selective inhibition of only one of the pathways in a tumor cell often leads to a limited response and, subsequently, to the emergence of resistance. Therefore, to increase the overall effectiveness of antitumor drugs, it is advisable to use multitarget agents that can simultaneously suppress several key processes in the tumor cell. This review is focused on a group of plant-derived natural compounds that simultaneously target different pathways of cancer-associated metabolism, including aerobic glycolysis, respiration, glutaminolysis, one-carbon metabolism, de novo lipogenesis, and β-oxidation of fatty acids. We discuss only those compounds that display inhibitory activity against several metabolic pathways as well as a number of important signaling pathways in cancer. Information about their pharmacokinetics in animals and humans is also presented. Taken together, a number of known plant-derived compounds may target multiple metabolic and signaling pathways in various malignancies, something that bears great potential for the further improvement of antineoplastic therapy.
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Affiliation(s)
- Oleg Shuvalov
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Yulia Kirdeeva
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Alexandra Daks
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Olga Fedorova
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Sergey Parfenyev
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland;
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
| | - Nickolai A. Barlev
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 20000, Kazakhstan
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Ren LL, Mao T, Meng P, Zhang L, Wei HY, Tian ZB. Glutamine addiction and therapeutic strategies in pancreatic cancer. World J Gastrointest Oncol 2023; 15:1852-1863. [PMID: 38077649 PMCID: PMC10701242 DOI: 10.4251/wjgo.v15.i11.1852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/06/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.
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Affiliation(s)
- Lin-Lin Ren
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Pin Meng
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Li Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Hong-Yun Wei
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Zi-Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
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Hu SS, Han Y, Tan TY, Chen H, Gao JW, Wang L, Yang MH, Zhao L, Wang YQ, Ding YQ, Wang S. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis. JCI Insight 2023; 8:e167874. [PMID: 37937641 PMCID: PMC10721270 DOI: 10.1172/jci.insight.167874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 09/20/2023] [Indexed: 11/09/2023] Open
Abstract
Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
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Affiliation(s)
- Sha-Sha Hu
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yue Han
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Tian-Yuan Tan
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Hui Chen
- Department of Pathology, Nanfang Hospital, and
| | - Jia-Wen Gao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lan Wang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Min-Hui Yang
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Li Zhao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yi-Qing Wang
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Shuang Wang
- Department of Pathology, Nanfang Hospital, and
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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35
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Zhang J, Darman L, Hassan MS, Von Holzen U, Awasthi N. Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review). Oncol Rep 2023; 50:206. [PMID: 37800636 PMCID: PMC10570661 DOI: 10.3892/or.2023.8643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/24/2023] [Indexed: 10/07/2023] Open
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in solid tumors. More than 90% of pancreatic ductal adenocarcinoma (PDAC) are driven by mutations in the KRAS gene, suggesting the importance of targeting this oncogene in PDAC. Initial efforts to target KRAS have been unsuccessful due to its small size, high affinity for guanosine triphosphate/guanosine diphosphate, and lack of distinct drug‑binding pockets. Therefore, much of the focus has been directed at inhibiting the activation of major signaling pathways downstream of KRAS, most notably the PI3K/AKT and RAF/MAPK pathways, using tyrosine kinase inhibitors and monoclonal antibodies. While preclinical studies showed promising results, clinical data using the inhibitors alone and in combination with other standard therapies have shown limited practicality, largely due to the lack of efficacy and dose‑limiting toxicities. Recent therapeutic approaches for KRAS‑driven tumors focus on mutation‑specific drugs such as selective KRASG12C inhibitors and son of sevenless 1 pan‑KRAS inhibitors. While KRASG12C inhibitors showed great promise against patients with non‑small cell lung cancer (NSCLC) harboring KRASG12C mutations, they were not efficacious in PDAC largely because the major KRAS mutant isoforms in PDAC are G12D, G12V, and G12R. As a result, KRASG12D and pan‑KRAS inhibitors are currently under investigation as potential therapeutic options for PDAC. The present review summarized the importance of KRAS oncogenic signaling, challenges in its targeting, and preclinical and clinical targeted agents including recent direct KRAS inhibitors for blocking KRAS signaling in PDAC.
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Affiliation(s)
- Joshua Zhang
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Lily Darman
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Md Sazzad Hassan
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
| | - Urs Von Holzen
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
- Goshen Center for Cancer Care, Goshen, IN 46526, USA
- University of Basel School of Medicine, 4056 Basel, Switzerland
| | - Niranjan Awasthi
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
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Wang Q, Tian Y, Yao M, Fu J, Wang L, Zhu Y. Bimetallic Organic Frameworks of High Piezovoltage for Sono-Piezo Dynamic Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2301784. [PMID: 37432882 DOI: 10.1002/adma.202301784] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/21/2023] [Accepted: 07/10/2023] [Indexed: 07/13/2023]
Abstract
Piezoelectric materials produce charges to directly act on cancer medium or promote the generation of reactive oxygen species (ROS) for novel tumor therapy triggered by sonography. Currently, piezoelectric sonosensitizers are mainly used to catalyze ROS generation by the band-tilting effect for sonodynamic therapy. However, it remains a challenge for piezoelectric sonosensitizers to produce high piezovoltages to overcome the bandgap barrier for direct charge generation. Herein, Mn-Ti bimetallic organic framework tetragonal nanosheets (MT-MOF TNS) are designed to produce high piezovoltages for novel sono-piezo (SP)-dynamic therapy (SPDT) with remarkable antitumor efficacy in vitro and in vivo. The MT-MOF TNS comprise non-centrosymmetric secondary building units of Mn-Ti-oxo cyclic octamers with charge heterogeneous components for piezoelectricity. The MT-MOF TNS promotes strong sonocavitation to induce piezoelectric effect with a high SP voltage (2.9 V) in situ, to directly excite charges, which is validated by SP-excited luminescence spectrometry. The SP voltage and charges depolarize the mitochondrial and plasma membrane potentials and cause ROS overproduction and serious tumor cell damage. Importantly, MT-MOF TNS can be decorated with targeting molecules and chemotherapeutics for more severe tumor regression by combining SPDT with chemodynamic therapy and chemotherapy. This report develops a fascinating MT-MOF piezoelectric nano-semiconductor and provides an efficient SPDT strategy for tumor treatment.
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Affiliation(s)
- Qiqi Wang
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yue Tian
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Meng Yao
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingke Fu
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Lianzhou Wang
- Nanomaterials Centre, School of Chemical Engineering, and Australian Institute of Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Yingchun Zhu
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China
- Center of Materials Science and Optoelectronics Engineer, University of Chinese Academy of Sciences, Beijing, 100049, China
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Rocca C, Soda T, De Francesco EM, Fiorillo M, Moccia F, Viglietto G, Angelone T, Amodio N. Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer. J Transl Med 2023; 21:635. [PMID: 37726810 PMCID: PMC10507834 DOI: 10.1186/s12967-023-04498-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 09/01/2023] [Indexed: 09/21/2023] Open
Abstract
A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.
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Affiliation(s)
- Carmine Rocca
- Cellular and Molecular Cardiovascular Pathophysiology Laboratory, Department of Biology, E and E.S. (DiBEST), University of Calabria, Arcavacata di Rende, 87036, Cosenza, Italy
| | - Teresa Soda
- Department of Health Science, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Ernestina Marianna De Francesco
- Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122, Catania, Italy
| | - Marco Fiorillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy
| | - Francesco Moccia
- Laboratory of General Physiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100, Pavia, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100, Catanzaro, Italy
| | - Tommaso Angelone
- Cellular and Molecular Cardiovascular Pathophysiology Laboratory, Department of Biology, E and E.S. (DiBEST), University of Calabria, Arcavacata di Rende, 87036, Cosenza, Italy.
- National Institute of Cardiovascular Research (I.N.R.C.), 40126, Bologna, Italy.
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100, Catanzaro, Italy.
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Tavares-Valente D, Cannone S, Greco MR, Carvalho TMA, Baltazar F, Queirós O, Agrimi G, Reshkin SJ, Cardone RA. Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell. Cancers (Basel) 2023; 15:3868. [PMID: 37568684 PMCID: PMC10417137 DOI: 10.3390/cancers15153868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
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Affiliation(s)
- Diana Tavares-Valente
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Stefania Cannone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Tiago Miguel Amaral Carvalho
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Gennaro Agrimi
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
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Perazzoli G, García-Valdeavero OM, Peña M, Prados J, Melguizo C, Jiménez-Luna C. Evaluating Metabolite-Based Biomarkers for Early Diagnosis of Pancreatic Cancer: A Systematic Review. Metabolites 2023; 13:872. [PMID: 37512579 PMCID: PMC10384620 DOI: 10.3390/metabo13070872] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/13/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with five-year survival rates around 10%. The only curative option remains complete surgical resection, but due to the delay in diagnosis, less than 20% of patients are eligible for surgery. Therefore, discovering diagnostic biomarkers for early detection is crucial for improving clinical outcomes. Metabolomics has become a powerful technology for biomarker discovery, and several metabolomic-based panels have been proposed for PDAC diagnosis, but these advances have not yet been translated into the clinic. Therefore, this review focused on summarizing metabolites identified for the early diagnosis of PDAC in the last five years. Bibliographic searches were performed in the PubMed, Scopus and WOS databases, using the terms "Biomarkers, Tumor", "Pancreatic Neoplasms", "Early Diagnosis", "Metabolomics" and "Lipidome" (January 2018-March 2023), and resulted in the selection of fourteen original studies that compared PDAC patients with subjects with other pancreatic diseases. These investigations showed amino acid and lipid metabolic pathways as the most commonly altered, reflecting their potential for biomarker research. Furthermore, other relevant metabolites such as glucose and lactate were detected in the pancreas tissue and body fluids from PDAC patients. Our results suggest that the use of metabolomics remains a robust approach to improve the early diagnosis of PDAC. However, these studies showed heterogeneity with respect to the metabolomics techniques used and further studies will be needed to validate the clinical utility of these biomarkers.
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Affiliation(s)
- Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto Biosanitario de Granada (ibs.GRANADA), 18014 Granada, Spain
| | - Olga M García-Valdeavero
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
| | - Mercedes Peña
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto Biosanitario de Granada (ibs.GRANADA), 18014 Granada, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto Biosanitario de Granada (ibs.GRANADA), 18014 Granada, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto Biosanitario de Granada (ibs.GRANADA), 18014 Granada, Spain
| | - Cristina Jiménez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto Biosanitario de Granada (ibs.GRANADA), 18014 Granada, Spain
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40
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Xue Z, Wang J, Wang Z, Liu J, Zhao J, Liu X, Zhang Y, Liu G, Zhao Z, Li W, Zhang Q, Li X, Huang B, Wang X. SLC25A32 promotes malignant progression of glioblastoma by activating PI3K-AKT signaling pathway. BMC Cancer 2023; 23:589. [PMID: 37365560 DOI: 10.1186/s12885-023-11097-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/21/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Solute carrier family 25 member 32 (SLC25A32) is an important member of SLC25A family and plays a role in folate transport metabolism. However, the mechanism and function of SLC25A32 in the progression of human glioblastoma (GBM) remain unclear. METHODS In this study, folate related gene analysis was performed to explore gene expression profiles in low-grade glioma (LGG) and GBM. Western blotting, real-time quantitative PCR (qRT-PCR), and immunohistochemistry (IHC) were used to confirm the expression levels of SLC25A32 in GBM tissues and cell lines. CCK-8 assays, colony formation assays, and Edu assays were performed to assess the role of SLC25A32 on proliferation in GBM in vitro. A 3D sphere invasion assay and an ex vivo co-culture invasion model were performed to assess the effects of SLC25A32 on invasion in GBM. RESULTS Elevated expression of SLC25A32 was observed in GBM, and high SLC25A32 expression was associated with a high glioma grade and poorer prognosis. Immunohistochemistry performed with anti-SLC25A32 on samples from an independent cohort of patients confirmed these results. Knockdown of SLC25A32 inhibited the proliferation and invasion of GBM cells, but overexpression of SLC25A32 significantly promoted cell growth and invasion. These effects were mainly due to the activation of the PI3K-AKT-mTOR signaling pathway. CONCLUSION Our study demonstrated that SLC25A32 plays a significant role in promoting the malignant phenotype of GBM. Therefore, SLC25A32 can be used as an independent prognostic factor in patients with GBM, providing a new target for the comprehensive treatment of GBM.
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Affiliation(s)
- Zhiwei Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Jiwei Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Zide Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Junzhi Liu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Jiangli Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Xuchen Liu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Yan Zhang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Guowei Liu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Zhimin Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Wenjie Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Qing Zhang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Bin Huang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China
| | - Xinyu Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China.
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China.
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Di Molfetta D, Cannone S, Greco MR, Caroppo R, Piccapane F, Carvalho TMA, Altamura C, Saltarella I, Tavares Valente D, Desaphy JF, Reshkin SJ, Cardone RA. ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells. Int J Mol Sci 2023; 24:10632. [PMID: 37445810 DOI: 10.3390/ijms241310632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/07/2023] [Accepted: 06/17/2023] [Indexed: 07/15/2023] Open
Abstract
Intracellular pH (pHi) regulation is a challenge for the exocrine pancreas, where the luminal secretion of bicarbonate-rich fluid is accompanied by interstitial flows of acid. This acid-base transport requires a plethora of ion transporters, including bicarbonate transporters and the Na+/H+ exchanger isoform 1 (NHE1), which are dysregulated in Pancreatic Ductal Adenocarcinoma (PDAC). PDAC progression is favored by a Collagen-I rich extracellular matrix (ECM) which exacerbates the physiological interstitial acidosis. In organotypic cultures of normal human pancreatic cells (HPDE), parenchymal cancer cells (CPCs) and cancer stem cells (CSCs) growing on matrices reproducing ECM changes during progression, we studied resting pHi, the pHi response to fluxes of NaHCO3 and acidosis and the role of NHE1 in pHi regulation. Our findings show that: (i) on the physiological ECM, HPDE cells have the most alkaline pHi, followed by CSCs and CPCs, while a Collagen I-rich ECM reverses the acid-base balance in cancer cells compared to normal cells; (ii) both resting pHi and pHi recovery from an acid load are reduced by extracellular NaHCO3, especially in HPDE cells on a normal ECM; (iii) cancer cell NHE1 activity is less affected by NaHCO3. We conclude that ECM composition and the fluctuations of pHe cooperate to predispose pHi homeostasis towards the presence of NaHCO3 gradients similar to that expected in the tumor.
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Affiliation(s)
- Daria Di Molfetta
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Stefania Cannone
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Rosa Caroppo
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Francesca Piccapane
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
| | | | - Concetta Altamura
- Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Ilaria Saltarella
- Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Diana Tavares Valente
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - Jean Francois Desaphy
- Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Stephan J Reshkin
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy
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Jones SA, Gogoi P, Ruprecht JJ, King MS, Lee Y, Zögg T, Pardon E, Chand D, Steimle S, Copeman DM, Cotrim CA, Steyaert J, Crichton PG, Moiseenkova-Bell V, Kunji ER. Structural basis of purine nucleotide inhibition of human uncoupling protein 1. SCIENCE ADVANCES 2023; 9:eadh4251. [PMID: 37256948 PMCID: PMC10413660 DOI: 10.1126/sciadv.adh4251] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 04/24/2023] [Indexed: 06/02/2023]
Abstract
Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.
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Affiliation(s)
- Scott A. Jones
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building, Cambridge CB2 0XY, UK
| | - Prerana Gogoi
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, 10-124 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5158, USA
| | - Jonathan J. Ruprecht
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building, Cambridge CB2 0XY, UK
| | - Martin S. King
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building, Cambridge CB2 0XY, UK
| | - Yang Lee
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building, Cambridge CB2 0XY, UK
| | - Thomas Zögg
- VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, B-1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
| | - Els Pardon
- VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, B-1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
| | - Deepak Chand
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building, Cambridge CB2 0XY, UK
| | - Stefan Steimle
- Department of Biochemistry and Biophysics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Danielle M. Copeman
- Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
| | - Camila A. Cotrim
- Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
| | - Jan Steyaert
- VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, B-1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
| | - Paul G. Crichton
- Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
| | - Vera Moiseenkova-Bell
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, 10-124 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5158, USA
| | - Edmund R. S. Kunji
- MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building, Cambridge CB2 0XY, UK
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González-Moreno L, Santamaría-Cano A, Paradela A, Martínez-Chantar ML, Martín MÁ, Pérez-Carreras M, García-Picazo A, Vázquez J, Calvo E, González-Aseguinolaza G, Saheki T, del Arco A, Satrústegui J, Contreras L. Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. Mol Genet Metab Rep 2023; 35:100967. [PMID: 36967723 PMCID: PMC10031141 DOI: 10.1016/j.ymgmr.2023.100967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/18/2023] Open
Abstract
The deficiency of CITRIN, the liver mitochondrial aspartate-glutamate carrier (AGC), is the cause of four human clinical phenotypes, neonatal intrahepatic cholestasis caused by CITRIN deficiency (NICCD), silent period, failure to thrive and dyslipidemia caused by CITRIN deficiency (FTTDCD), and citrullinemia type II (CTLN2). Clinical symptoms can be traced back to disruption of the malate-aspartate shuttle due to the lack of citrin. A potential therapy for this condition is the expression of aralar, the AGC present in brain, to replace citrin. To explore this possibility we have first verified that the NADH/NAD+ ratio increases in hepatocytes from citrin(-/-) mice, and then found that exogenous aralar expression reversed the increase in NADH/NAD+ observed in these cells. Liver mitochondria from citrin (-/-) mice expressing liver specific transgenic aralar had a small (~ 4-6 nmoles x mg prot-1 x min-1) but consistent increase in malate aspartate shuttle (MAS) activity over that of citrin(-/-) mice. These results support the functional replacement between AGCs in the liver. To explore the significance of AGC replacement in human therapy we studied the relative levels of citrin and aralar in mouse and human liver through absolute quantification proteomics. We report that mouse liver has relatively high aralar levels (citrin/aralar molar ratio of 7.8), whereas human liver is virtually devoid of aralar (CITRIN/ARALAR ratio of 397). This large difference in endogenous aralar levels partly explains the high residual MAS activity in liver of citrin(-/-) mice and why they fail to recapitulate the human disease, but supports the benefit of increasing aralar expression to improve the redox balance capacity of human liver, as an effective therapy for CITRIN deficiency.
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Key Words
- (BNGE), Blue native gel electrophoresis
- AGC, aspartate-glutamate carrier
- AQUA, Absolute Quantification methods
- Aspartate-glutamate carrier
- CD, CITRIN Deficiency
- CTNL2, citrullinemia type II
- Citrin deficiency
- DAB, 3,3-diaminobenzidine
- FBS, Fetal Bovine serum
- FTTDCD, failure to thrive and dyslipidemia caused by CITRIN Deficiency
- GOT, aspartate transaminase
- GPD2, mitochondrial glycerol phosphate dehydrogenase
- GPS, glycerol phosphate shuttle
- Hepatocyte
- IM, imaging medium
- LC-MS, liquid chromatography mass spectrometry
- LNP, lipid nanoparticles
- MAS, malate aspartate shuttle
- Malate-aspartate shuttle
- Mitochondria
- NAA, N-Acetyl-aspartate
- NICCD, neonatal intrahepatic cholestasis caused by CITRIN Deficiency
- OXPHOS, oxidative phosphorylation
- PFA, paraformaldehyde
- PRM, parallel reaction monitoring
- SDS, sodium dodecyl sulfate
- TBS, Tris-Buffered saline.
- hCitrin, human citrin
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Affiliation(s)
- Luis González-Moreno
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Instituto Universitario de Biología Molecular, (IUBM), and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Andrea Santamaría-Cano
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Instituto Universitario de Biología Molecular, (IUBM), and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Alberto Paradela
- Centro Nacional de Biotecnología (CNB), CSIC. C/Darwin 3, 28049 Madrid, Spain
| | - María Luz Martínez-Chantar
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Miguel Á. Martín
- Grupo Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain
- Servicio de Genética, Hospital Universitario 12 de Octubre, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain
| | | | - Alberto García-Picazo
- Departamento de Cirugía General Aparato Digestivo, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Jesús Vázquez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Enrique Calvo
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Gloria González-Aseguinolaza
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
- IdiSNA Navarra Institute for Health Research, 31008 Pamplona, Spain
| | | | - Araceli del Arco
- Instituto Universitario de Biología Molecular, (IUBM), and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla la Mancha, Toledo 45071, Spain
- Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina, Toledo 45071, Spain
| | - Jorgina Satrústegui
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Instituto Universitario de Biología Molecular, (IUBM), and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Laura Contreras
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Instituto Universitario de Biología Molecular, (IUBM), and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049 Madrid, Spain
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Gorgoglione R, Seccia R, Ahmed A, Vozza A, Capobianco L, Lodi A, Marra F, Paradies E, Palmieri L, Coppola V, Dolce V, Fiermonte G. Generation of a Yeast Cell Model Potentially Useful to Identify the Mammalian Mitochondrial N-Acetylglutamate Transporter. Biomolecules 2023; 13:biom13050808. [PMID: 37238678 DOI: 10.3390/biom13050808] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
The human mitochondrial carrier family (MCF) consists of 53 members. Approximately one-fifth of them are still orphans of a function. Most mitochondrial transporters have been functionally characterized by reconstituting the bacterially expressed protein into liposomes and transport assays with radiolabeled compounds. The efficacy of this experimental approach is constrained to the commercial availability of the radiolabeled substrate to be used in the transport assays. A striking example is that of N-acetylglutamate (NAG), an essential regulator of the carbamoyl synthetase I activity and the entire urea cycle. Mammals cannot modulate mitochondrial NAG synthesis but can regulate the levels of NAG in the matrix by exporting it to the cytosol, where it is degraded. The mitochondrial NAG transporter is still unknown. Here, we report the generation of a yeast cell model suitable for identifying the putative mammalian mitochondrial NAG transporter. In yeast, the arginine biosynthesis starts in the mitochondria from NAG which is converted to ornithine that, once transported into cytosol, is metabolized to arginine. The deletion of ARG8 makes yeast cells unable to grow in the absence of arginine since they cannot synthetize ornithine but can still produce NAG. To make yeast cells dependent on a mitochondrial NAG exporter, we moved most of the yeast mitochondrial biosynthetic pathway to the cytosol by expressing four E. coli enzymes, argB-E, able to convert cytosolic NAG to ornithine. Although argB-E rescued the arginine auxotrophy of arg8∆ strain very poorly, the expression of the bacterial NAG synthase (argA), which would mimic the function of a putative NAG transporter increasing the cytosolic levels of NAG, fully rescued the growth defect of arg8∆ strain in the absence of arginine, demonstrating the potential suitability of the model generated.
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Affiliation(s)
- Ruggiero Gorgoglione
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Roberta Seccia
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Amer Ahmed
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Angelo Vozza
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Loredana Capobianco
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Alessia Lodi
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA
- Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA
| | - Federica Marra
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Eleonora Paradies
- CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), 70125 Bari, Italy
| | - Luigi Palmieri
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
| | - Vincenzo Coppola
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Vincenza Dolce
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Giuseppe Fiermonte
- Department of Bioscience, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
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45
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Segalés J, Sánchez-Martín C, Pujol-Morcillo A, Martín-Ruiz M, de Los Santos P, Lobato-Alonso D, Oliver E, Rial E. Role of UCP2 in the Energy Metabolism of the Cancer Cell Line A549. Int J Mol Sci 2023; 24:ijms24098123. [PMID: 37175829 PMCID: PMC10179244 DOI: 10.3390/ijms24098123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/21/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
The uncoupling protein UCP2 is a mitochondrial carrier for which transport activity remains controversial. The physiological contexts in which UCP2 is expressed have led to the assumption that, like UCP1, it uncouples oxidative phosphorylation and thereby reduces the generation of reactive oxygen species. Other reports have involved UCP2 in the Warburg effect, and results showing that UCP2 catalyzes the export of matrix C4 metabolites to facilitate glutamine utilization suggest that the carrier could be involved in the metabolic adaptations required for cell proliferation. We have examined the role of UCP2 in the energy metabolism of the lung adenocarcinoma cell line A549 and show that UCP2 silencing decreased the basal rate of respiration, although this inhibition was not compensated by an increase in glycolysis. Silencing did not lead to either changes in proton leakage, as determined by the rate of respiration in the absence of ATP synthesis, or changes in the rate of formation of reactive oxygen species. The decrease in energy metabolism did not alter the cellular energy charge. The decreased cell proliferation observed in UCP2-silenced cells would explain the reduced cellular ATP demand. We conclude that UCP2 does not operate as an uncoupling protein, whereas our results are consistent with its activity as a C4-metabolite carrier involved in the metabolic adaptations of proliferating cells.
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Affiliation(s)
- Jessica Segalés
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Carlos Sánchez-Martín
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Aleida Pujol-Morcillo
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Marta Martín-Ruiz
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Patricia de Los Santos
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Daniel Lobato-Alonso
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Eduardo Oliver
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Eduardo Rial
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
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Zhang Z, Zhang H, Liao X, Tsai HI. KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression. Front Cell Dev Biol 2023; 11:1147676. [PMID: 37152291 PMCID: PMC10157181 DOI: 10.3389/fcell.2023.1147676] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It has a poor response to conventional therapy and has an extremely poor 5-year survival rate. PDAC is driven by multiple oncogene mutations, with the highest mutation frequency being observed in KRAS. The KRAS protein, which binds to GTP, has phosphokinase activity, which further activates downstream effectors. KRAS mutation contributes to cancer cell proliferation, metabolic reprogramming, immune escape, and therapy resistance in PDAC, acting as a critical driver of the disease. Thus, KRAS mutation is positively associated with poorer prognosis in pancreatic cancer patients. This review focus on the KRAS mutation patterns in PDAC, and further emphases its role in signal transduction, metabolic reprogramming, therapy resistance and prognosis, hoping to provide KRAS target therapy strategies for PDAC.
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Affiliation(s)
- Zining Zhang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Heng Zhang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiang Liao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hsiang-i Tsai
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Murali R, Balasubramaniam V, Srinivas S, Sundaram S, Venkatraman G, Warrier S, Dharmarajan A, Gandhirajan RK. Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence. Metabolites 2023; 13:metabo13040560. [PMID: 37110218 PMCID: PMC10141515 DOI: 10.3390/metabo13040560] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.
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Affiliation(s)
- Roopak Murali
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Vaishnavi Balasubramaniam
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Satish Srinivas
- Department of Radiation Oncology, Sri Ramachandra Medical College & Research Institute, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai 600116, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College & Research Institute, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai 600116, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560065, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560065, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
- Stem Cell and Cancer Biology Laboratory, Curtin University, Perth, WA 6102, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6102, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
| | - Rajesh Kumar Gandhirajan
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
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48
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Fu S, Xu S, Zhang S. The role of amino acid metabolism alterations in pancreatic cancer: From mechanism to application. Biochim Biophys Acta Rev Cancer 2023; 1878:188893. [PMID: 37015314 DOI: 10.1016/j.bbcan.2023.188893] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/13/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023]
Abstract
The incidence of pancreatic cancer is increasing in both developed and developing Nations. In recent years, various research evidence suggested that reprogrammed metabolism may play a key role in pancreatic cancer tumorigenesis and development. Therefore, it has great potential as a diagnostic, prognostic and therapeutic target. Amino acid metabolism is deregulated in pancreatic cancer, and changes in amino acid metabolism can affect cancer cell status, systemic metabolism in malignant tumor patients and mistakenly involved in different biological processes including stemness, proliferation and growth, invasion and migration, redox state maintenance, autophagy, apoptosis and even tumor microenvironment interaction. Generally, the above effects are achieved through two pathways, energy metabolism and signal transduction. This review aims to highlight the current research progress on the abnormal alterations of amino acids metabolism in pancreatic cancer, how they affect tumorigenesis and development of pancreatic cancer and the application prospects of them as diagnostic, prognostic and therapeutic targets.
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Affiliation(s)
- Shenao Fu
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, PR China; Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China
| | - Shaokang Xu
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, PR China; Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China
| | - Shubing Zhang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, PR China.
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49
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Revskij D, Runst J, Umstätter C, Ehlers L, Rohde S, Zechner D, Bastian M, Müller-Hilke B, Fuellen G, Henze L, Murua Escobar H, Junghanss C, Kowald A, Walter U, Köhling R, Wolkenhauer O, Jaster R. Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice. Hepatobiliary Pancreat Dis Int 2023; 22:190-199. [PMID: 36549966 DOI: 10.1016/j.hbpd.2022.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. METHODS We took advantage of a model of accelerated aging, uncoupling protein 2-deficient (Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. RESULTS Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. CONCLUSIONS Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.
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Affiliation(s)
- Denis Revskij
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Jakob Runst
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Camilla Umstätter
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Luise Ehlers
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Sarah Rohde
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Dietmar Zechner
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Manuela Bastian
- Institute of Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Rostock, Germany
| | - Brigitte Müller-Hilke
- Facility for Cell Sorting and Cell Analysis and Institute of Immunology, Rostock University Medical Center, Rostock, Germany
| | - Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Larissa Henze
- Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, Germany
| | - Hugo Murua Escobar
- Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, Germany
| | - Christian Junghanss
- Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, Germany
| | - Axel Kowald
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Uwe Walter
- Department of Neurology, Rostock University Medical Center, Rostock, Germany
| | - Rüdiger Köhling
- Oscar Langendorff Institute of Physiology, Rostock University Medical Center, Rostock, Germany
| | - Olaf Wolkenhauer
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
| | - Robert Jaster
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany.
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50
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Yu L, He R, Cui Y. Characterization of tumor microenvironment and programmed death-related genes to identify molecular subtypes and drug resistance in pancreatic cancer. Front Pharmacol 2023; 14:1146280. [PMID: 37007021 PMCID: PMC10063807 DOI: 10.3389/fphar.2023.1146280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/09/2023] [Indexed: 03/19/2023] Open
Abstract
Background: Immunotherapy has been a key option for the treatment of many types of cancer. A positive response to immunotherapy is heavily dependent on tumor microenvironment (TME) interaction. However, in pancreatic adenocarcinoma (PAAD), the association between TME mode of action and immune cell infiltration and immunotherapy, clinical outcome remained unknown.Methods: We systematically evaluated 29 TME genes in PAAD signature. Molecular subtypes of distinct TME signatures in PAAD were characterized by consensus clustering. After this, we comprehensively analyzed their clinical features, prognosis, and immunotherapy/chemotherapy response using correlation analysis, Kaplan-Meier curves analysis, ssGSEA analysis. 12 programmed cell death (PCD) patterns were acquired from previous study. Differentially expressed genes (DEGs) were acquired based on differential analysis. Key genes affecting overall survival (OS) of PAAD were screened by COX regression analysis and used to develop a RiskScore evaluation model. Finally, we assessed the value of RiskScore in predicting prognosis and treatment response in PAAD.Results: We identified 3 patterns of TME-associated molecular subtypes (C1, C2, C3), and observed that clinicopathological characteristics, prognosis, pathway features and immune features, immunotherapy/chemosensitivity of patients were correlated with the TME related subtypes. C1 subtype was more sensitive to the four chemotherapeutic drugs. PCD patterns were more likely to occur at C2 or C3. At the same time, we also detected 6 key genes that could affect the prognosis of PAAD, and 5 genes expressions were closely associated to methylation level. Low-risk patients with high immunocompetence had favorable prognostic results and high immunotherapy benefit. Patients in the high-risk group were more sensitive to chemotherapeutic drugs. RiskScore related to TME was an independent prognostic factor for PAAD.Conclusion: Collectively, we identified a prognostic signature of TME in PAAD patients, which could help elucidate the specific mechanism of action of TME in tumors and help to explore more effective immunotherapy strategies.
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Affiliation(s)
- Liang Yu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Risheng He
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Yunfu Cui,
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