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Xu N, Lin H, Ding X, Wang P, Lin JM. Isotope tracing-assisted chip-based solid-phase extraction mass spectrometry for monitoring metabolic changes and vitamin D3 regulation in cells. Talanta 2025; 288:127754. [PMID: 39970803 DOI: 10.1016/j.talanta.2025.127754] [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: 01/13/2025] [Revised: 02/11/2025] [Accepted: 02/15/2025] [Indexed: 02/21/2025]
Abstract
Cellular metabolism is a dynamic and essential process, with alterations in metabolic pathways serving as hallmark features of cancer. In this study, we developed a chip-based solid-phase extraction mass spectrometry (Chip-SPE-MS) platform for high-sensitivity, high-throughput analysis of cellular metabolites and real-time tracking of metabolic fluxes. The system achieved detection limits ranging from 0.10 to 9.43 μmol/mL for various amino acids and organic acids, with excellent linearity (r ≥ 0.992). By incorporating isotope tracing, the platform enabled derivatization-free, real-time monitoring of 13C-labeled metabolites, such as lactic acid. Our analysis revealed significant metabolic differences between normal (L02) and cancerous (HepG2, HCT116) cells, including enhanced glycolytic activity and elevated lactate production in cancer cells. Furthermore, treatment with 1,25-dihydroxyvitamin D3 was shown to suppress glucose uptake and modulate metabolic activity in HCT116 cells, highlighting the regulatory effects of vitamin D3 on cancer metabolism. This study not only provides novel insights into the metabolic reprogramming associated with cancer but also demonstrates the potential of the Chip-SPE-MS platform as a powerful tool for real-time monitoring of dynamic metabolic processes. The findings have broad implications for cancer therapy and the study of metabolic diseases.
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Affiliation(s)
- Ning Xu
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Haifeng Lin
- Department of Bioengineering, Beijing Technology and Business University, Beijing, 100048, China
| | - Xiaodan Ding
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Peilong Wang
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
| | - Jin-Ming Lin
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China.
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Tian HP, Xiao ZX, Su BW, Li YX, Peng H, Meng CY. Impact of SLC16A8 on tumor microenvironment and angiogenesis in colorectal cancer: New therapeutic target insights. World J Gastrointest Oncol 2025; 17:99188. [DOI: 10.4251/wjgo.v17.i4.99188] [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: 07/16/2024] [Revised: 11/08/2024] [Accepted: 01/15/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND SLC16A8, a lactate efflux transporter, is upregulated in various cancers, but its effects on tumor microenvironments remain understudied. This research explores its role in colorectal cancer (CRC) and the impact on the associated microenvironment consisting of vascular endothelial cells.
AIM To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.
METHODS Hypoxic conditions prompted examination of SLC16A8 expression, glycolysis, lactate efflux, and Warburg effect correlations in CRC cell lines. Co-culture with HUVEC allowed for endothelial-mesenchymal transition (EndMT) characterization, revealing lactate efflux's influence. Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments, investigating tumor growth, blood vessel distribution, and signaling pathway alterations.
RESULTS SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression (P < 0.05). Under hypoxic conditions, HIF-1α induced SLC16A8 expression, leading to enhanced metabolic reprogramming and increased lactate production. siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes, including reduced glucose consumption and lactate production. Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells. In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth, reduced Ki67 expression, and decreased HIF-1α levels. Furthermore, SLC16A8 silencing led to decreased expression of key metabolic enzymes PKM2 and LDHA, indicating its role in glycolytic regulation.
CONCLUSION Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.
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Affiliation(s)
- Hong-Peng Tian
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zhong-Xiang Xiao
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Bo-Wen Su
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yi-Xuan Li
- Department of Premarital and Prenatal Examination, Nanchong Shunqing District Maternal and Child Health Hospital, Nanchong 637000, Sichuan Province, China
| | - Hong Peng
- Department of Anorectal Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Chang-Yuan Meng
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
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3
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Ruan Z, Wang Y, Shi L, Yang XJ. Progress of research on glucose transporter proteins in hepatocellular carcinoma. World J Hepatol 2025; 17:104715. [DOI: 10.4254/wjh.v17.i3.104715] [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: 12/29/2024] [Revised: 02/02/2025] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs’ roles in HCC and to determine the most effective ways to translate these findings into clinical practice.
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Affiliation(s)
- Zheng Ruan
- The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yan Wang
- Division of Personnel, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
| | - Lei Shi
- Department of General Surgery, The Second people’s Hospital of Lanzhou, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Yang
- Department of General Surgery, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
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Song Q, Sui J, Yang Y, Zhang H, Ya L, Yang L. Fructose-1,6-bisphosphatase 1 in cancer: Dual roles, mechanistic insights, and therapeutic potential - A comprehensive review. Int J Biol Macromol 2025; 293:139273. [PMID: 39753180 DOI: 10.1016/j.ijbiomac.2024.139273] [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: 12/14/2024] [Revised: 12/22/2024] [Accepted: 12/26/2024] [Indexed: 01/07/2025]
Abstract
Fructose-1,6-bisphosphatase 1 (FBP1) is a key gluconeogenic enzyme that plays complex and context-dependent roles in cancer biology. This review comprehensively examines FBP1's dual functions as both a tumor suppressor and an oncogene across various cancer types. In many cancers, such as hepatocellular carcinoma, clear cell renal cell carcinoma, and lung cancer, downregulation of FBP1 contributes to tumor progression through metabolic reprogramming, promoting glycolysis, and altering the tumor microenvironment. Conversely, in certain contexts like breast and prostate cancers, FBP1 overexpression is associated with tumor promotion, indicating its oncogenic potential. The review explores FBP1's interactions with immune cells within the tumor microenvironment, influencing immune surveillance and tumor immune escape mechanisms. Additionally, FBP1 emerges as a promising diagnostic and prognostic biomarker, with expression levels correlating with patient outcomes in multiple cancers. Future therapeutic strategies targeting FBP1 are discussed, including inhibitors, activators, epigenetic modulation, and combination therapies, while addressing the challenges posed by its dual nature. Understanding the multifaceted roles of FBP1 offers valuable insights into cancer metabolism and opens avenues for personalized therapeutic interventions.
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Affiliation(s)
- Qinghang Song
- School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Jiazhen Sui
- School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Yuxuan Yang
- School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Huhu Zhang
- School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Li Ya
- School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Lina Yang
- School of Basic Medicine, Qingdao University, Qingdao 266071, China.
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5
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Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, Yao Y, Xu S, Ge S, Jia R. Lactate and lactylation in cancer. Signal Transduct Target Ther 2025; 10:38. [PMID: 39934144 DOI: 10.1038/s41392-024-02082-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: 06/28/2024] [Revised: 10/07/2024] [Accepted: 11/18/2024] [Indexed: 02/13/2025] Open
Abstract
Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.
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Affiliation(s)
- Jie Chen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Ziyue Huang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Ya Chen
- Department of Radiology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
| | - Hao Tian
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Peiwei Chai
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Yongning Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
| | - Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China
| | - Shiqiong Xu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, PR China.
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López-Cánovas JL, Naranjo-Martínez B, Diaz-Ruiz A. Fasting in combination with the cocktail Sorafenib:Metformin blunts cellular plasticity and promotes liver cancer cell death via poly-metabolic exhaustion. Cell Oncol (Dordr) 2025; 48:161-182. [PMID: 38990489 PMCID: PMC11850423 DOI: 10.1007/s13402-024-00966-2] [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: 05/31/2024] [Indexed: 07/12/2024] Open
Abstract
PURPOSE Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M). RESULTS Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death. CONCLUSION Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.
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Affiliation(s)
- Juan L López-Cánovas
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain
| | - Beatriz Naranjo-Martínez
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain
| | - Alberto Diaz-Ruiz
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain.
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain.
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Sumon MSI, Malluhi M, Anan N, AbuHaweeleh MN, Krzyslak H, Vranic S, Chowdhury MEH, Pedersen S. Integrative Stacking Machine Learning Model for Small Cell Lung Cancer Prediction Using Metabolomics Profiling. Cancers (Basel) 2024; 16:4225. [PMID: 39766124 PMCID: PMC11727543 DOI: 10.3390/cancers16244225] [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: 11/02/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 01/15/2025] Open
Abstract
Background: Small cell lung cancer (SCLC) is an extremely aggressive form of lung cancer, characterized by rapid progression and poor survival rates. Despite the importance of early diagnosis, the current diagnostic techniques are invasive and restricted. Methods: This study presents a novel stacking-based ensemble machine learning approach for classifying small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) using metabolomics data. The analysis included 191 SCLC cases, 173 NSCLC cases, and 97 healthy controls. Feature selection techniques identified significant metabolites, with positive ions proving more relevant. Results: For multi-class classification (control, SCLC, NSCLC), the stacking ensemble achieved 85.03% accuracy and 92.47 AUC using Support Vector Machine (SVM). Binary classification (SCLC vs. NSCLC) further improved performance, with ExtraTreesClassifier reaching 88.19% accuracy and 92.65 AUC. SHapley Additive exPlanations (SHAP) analysis revealed key metabolites like benzoic acid, DL-lactate, and L-arginine as significant predictors. Conclusions: The stacking ensemble approach effectively leverages multiple classifiers to enhance overall predictive performance. The proposed model effectively captures the complementary strengths of different classifiers, enhancing the detection of SCLC and NSCLC. This work accentuates the potential of combining metabolomics with advanced machine learning for non-invasive early lung cancer subtype detection, offering an alternative to conventional biopsy methods.
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Affiliation(s)
| | - Marwan Malluhi
- College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (M.M.); (M.N.A.); (S.V.)
| | - Noushin Anan
- Department of Electrical Engineering, Qatar University, Doha 2713, Qatar; (M.S.I.S.); (N.A.)
| | | | - Hubert Krzyslak
- Department of Clinical Biochemistry, Aalborg University Hospital, 9000 Aalborg, Denmark;
| | - Semir Vranic
- College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (M.M.); (M.N.A.); (S.V.)
| | | | - Shona Pedersen
- College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (M.M.); (M.N.A.); (S.V.)
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Abuduaini B, Jiyuan Z, Rehati A, Liang Z, Yunlin S. Regulation of Alternative Splicing of Lipid Metabolism Genes in Sepsis-Induced Liver Damage by RNA-Binding Proteins. Inflammation 2024; 47:1952-1968. [PMID: 38727856 PMCID: PMC11607010 DOI: 10.1007/s10753-024-02017-2] [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: 02/07/2024] [Revised: 03/23/2024] [Accepted: 03/31/2024] [Indexed: 11/30/2024]
Abstract
RNA binding proteins (RBPs) have the potential for transcriptional regulation in sepsis-induced liver injury, but precise functions remain unclear. Our aim is to conduct a genome-wide expression analysis of RBPs and illuminate changes in the regulation of alternative splicing in sepsis-induced liver injury. RNA-seq data on "sepsis and liver" from the publicly available NCBI data set was analyzed, and differentially expressed RBPs and alternative splicing events (ASEs) in the healthy and septic liver were identified. Co-expression analyses of sepsis-regulated RBPs and ASEs were performed. Models of sepsis were established to validate hepatic RBP gene expression patterns with different treatments. Pairwise analysis of gene expression profiles of sham, cecum ligation puncture (CLP), and CLP with dichloroacetate (CLPDCA) mice allowed 1208 differentially expressed genes (DEGs), of which 800 were up-regulated and 408 down-regulated, to be identified. DEGs were similar in both Sham and CLPDCA mice. The KEGG analysis showed that up-regulated genes as being involved in cytokine-cytokine receptor interaction and IL-17 signaling pathway and down-regulated genes in metabolic pathways. Differences in lipid metabolism-related alternative splicing events, including A3SS, were also found in CLP and CLPDCA compared with sham mice. Thirty-seven RBPs, including S100a11, Ads2, Fndc3b, Fn1, Ddx28, Car2, Cisd1, and Ptms, were differentially expressed in CLP mice and the regulated alternative splicing genes(RASG) with the RBP shown to be enriched in lipid metabolic and oxidation-reduction-related processes by GO functional analysis. In KEEG analysis the RASG mainly enriched in metabolic pathway. The models of sepsis were constructed with different treatment groups, and S100a11 expression in the CLP group found to be higher than in the sham group, a change that was reversed by DCA. The alternative splicing ratio of Srebf1 and Cers2 decreased compared with the sham group increased after DCA treatment. Abnormal profiles of gene expression and alternative splicing were associated with sepsis-induced liver injury. Unusual expression of RBPs, such as S100a11, may regulate alternative splicing of lipid metabolism-associated genes, such as Srebf1 and Cers2, in the septic liver. RBPs may constitute potential treatment targets for sepsis-induced liver injury.
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Affiliation(s)
- Buzukela Abuduaini
- Department of Intensive Care Unit, The First Affiliated Hospital of Xinjiang Medical University, 393 South Li Yu Shan Road, Ürümqi, 830054, Xinjiang, China
| | - Zhang Jiyuan
- First Clinical institute of Xinjiang Medical University, Ürümqi, 830054, Xinjiang, China
| | - Aliya Rehati
- Department of Gastroenternology, The First Affiliated Hospital of Xinjiang Medical University, 393 South Li Yu Shan Road, Ürümqi, 830054, Xinjiang, China
| | - Zhao Liang
- Department of General Surgery, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, 830054, Xinjiang, China
| | - Song Yunlin
- Department of Intensive Care Unit, The First Affiliated Hospital of Xinjiang Medical University, 393 South Li Yu Shan Road, Ürümqi, 830054, Xinjiang, China.
- Department of Intensive Care Unit, The First Affiliated Hospital of Xinjiang Medical University,State Key Laboratory of Pathogenesis, Prevention and Treatment of high Incidence Diseases in Central Asia, 393 South Li Yu Shan Road, Ürümqi, 830054, Xinjiang, China.
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Okano Y, Yamauchi T, Fukuzaki R, Tsuruta A, Yoshida Y, Tsurudome Y, Ushijima K, Matsunaga N, Koyanagi S, Ohdo S. Oncogenic accumulation of cysteine promotes cancer cell proliferation by regulating the translation of D-type cyclins. J Biol Chem 2024; 300:107890. [PMID: 39413876 DOI: 10.1016/j.jbc.2024.107890] [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: 05/04/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/18/2024] Open
Abstract
Malignant cells exhibit a high demand for amino acids to sustain their abnormal proliferation. Particularly, the intracellular accumulation of cysteine is often observed in cancer cells. Previous studies have shown that deprivation of intracellular cysteine in cancer cells results in the accumulation of lipid peroxides in the plasma membrane and induction of ferroptotic cell death, indicating that cysteine plays a critical role in the suppression of ferroptosis. Herein, we found that the oncogenic accumulation of cysteine also contributes to cancer cell proliferation by promoting the cell cycle progression, which is independent of its suppressive effect on ferroptosis. The growth ability of four types of cancer cells, including murine hepatocarcinoma cells, but not of primary hepatocytes, were dependent on the exogenous supply of cysteine. Deprivation of intracellular cysteine in cancer cells induced cell cycle arrest at the G0/G1 phase, accompanied by a decrease in the expression of cyclin D1 and D2 proteins. The cysteine deprivation-induced decrease in D-type cyclin expression was associated with the upregulation of eukaryotic translation initiation factor 4E binding protein 1, which represses the translation of cyclin D1 and D2 proteins by binding to eukaryotic translation initiation factor 4E. Similar results were observed in hepatocarcinoma cells treated with erastin, an inhibitor of cystine/glutamate antiporter, xCT. These findings reveal an unappreciated role of cysteine in regulating the growth of malignant cancer cells and deepen our understanding of the cytotoxic effect of xCT inhibitor to prevent cancer cell proliferation.
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Affiliation(s)
- Yumi Okano
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoaki Yamauchi
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Runa Fukuzaki
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akito Tsuruta
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuya Yoshida
- Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuya Tsurudome
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyoonoda, Yamaguchi, Japan
| | - Kentaro Ushijima
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyoonoda, Yamaguchi, Japan
| | - Naoya Matsunaga
- Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoru Koyanagi
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
| | - Shigehiro Ohdo
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
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10
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Ewald J, He Z, Dimitriew W, Schuster S. Including glutamine in a resource allocation model of energy metabolism in cancer and yeast cells. NPJ Syst Biol Appl 2024; 10:77. [PMID: 39025861 PMCID: PMC11258256 DOI: 10.1038/s41540-024-00393-x] [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: 11/13/2023] [Accepted: 06/10/2024] [Indexed: 07/20/2024] Open
Abstract
Energy metabolism is crucial for all living cells, especially during fast growth or stress scenarios. Many cancer and activated immune cells (Warburg effect) or yeasts (Crabtree effect) mostly rely on aerobic glucose fermentation leading to lactate or ethanol, respectively, to generate ATP. In recent years, several mathematical models have been proposed to explain the Warburg effect on theoretical grounds. Besides glucose, glutamine is a very important substrate for eukaryotic cells-not only for biosynthesis, but also for energy metabolism. Here, we present a minimal constraint-based stoichiometric model for explaining both the classical Warburg effect and the experimentally observed respirofermentation of glutamine (WarburQ effect). We consider glucose and glutamine respiration as well as the respective fermentation pathways. Our resource allocation model calculates the ATP production rate, taking into account enzyme masses and, therefore, pathway costs. While our calculation predicts glucose fermentation to be a superior energy-generating pathway in human cells, different enzyme characteristics in yeasts reduce this advantage, in some cases to such an extent that glucose respiration is preferred. The latter is observed for the fungal pathogen Candida albicans, which is a known Crabtree-negative yeast. Further, optimization results show that glutamine is a valuable energy source and important substrate under glucose limitation, in addition to its role as a carbon and nitrogen source of biomass in eukaryotic cells. In conclusion, our model provides insights that glutamine is an underestimated fuel for eukaryotic cells during fast growth and infection scenarios and explains well the observed parallel respirofermentation of glucose and glutamine in several cell types.
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Affiliation(s)
- Jan Ewald
- Department of Bioinformatics, Friedrich Schiller University of Jena, Ernst-Abbe-Platz 2, 07743, Jena, Germany
- Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI) Dresden/Leipzig, Leipzig University, Humboldtstraße 25, 04105, Leipzig, Germany
| | - Ziyang He
- Department of Bioinformatics, Friedrich Schiller University of Jena, Ernst-Abbe-Platz 2, 07743, Jena, Germany
| | - Wassili Dimitriew
- Department of Bioinformatics, Friedrich Schiller University of Jena, Ernst-Abbe-Platz 2, 07743, Jena, Germany
| | - Stefan Schuster
- Department of Bioinformatics, Friedrich Schiller University of Jena, Ernst-Abbe-Platz 2, 07743, Jena, Germany.
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Kim JY, Jung JH, Jung S, Lee S, Lee HA, Ouh YT, Hong SH. Glyoxalase 1: Emerging biomarker and therapeutic target in cervical cancer progression. PLoS One 2024; 19:e0299345. [PMID: 38870176 PMCID: PMC11175447 DOI: 10.1371/journal.pone.0299345] [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: 02/28/2024] [Accepted: 05/26/2024] [Indexed: 06/15/2024] Open
Abstract
INTRODUCTION Cervical cancer presents a significant global health challenge, disproportionately impacting underserved populations with limited access to healthcare. Early detection and effective management are vital in addressing this public health concern. This study focuses on Glyoxalase-1 (GLO1), an enzyme crucial for methylglyoxal detoxification, in the context of cervical cancer. METHODS We assessed GLO1 expression in cervical cancer patient samples using immunohistochemistry. In vitro experiments using HeLa cells were conducted to evaluate the impact of GLO1 inhibition on cell viability and migration. Single-cell RNA sequencing (scRNA-seq) and gene set variation analysis were utilized to investigate the role of GLO1 in the metabolism of cervical cancer. Additionally, public microarray data were analyzed to determine GLO1 expression across various stages of cervical cancer. RESULTS Our analysis included 58 cervical cancer patients, and showed that GLO1 is significantly upregulated in cervical cancer tissues compared to normal cervical tissues, independent of pathological findings and disease stage. In vitro experiments indicated that GLO1 inhibition by S-p-bromobenzylglutathione cyclopentyl diester decreased cell viability and migration in cervical cancer cell lines. Analyses of scRNA-seq data and public gene expression datasets corroborated the overexpression of GLO1 and its involvement in cancer metabolism, particularly glycolysis. An examination of expression data from precancerous lesions revealed a progressive increase in GLO1 expression from normal tissue to invasive cervical cancer. CONCLUSIONS This study highlights the critical role of GLO1 in the progression of cervical cancer, presenting it as a potential biomarker and therapeutic target. These findings contribute valuable insights towards personalized treatment approaches and augment the ongoing efforts to combat cervical cancer. Further research is necessary to comprehensively explore GLO1's potential in clinical applications.
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Affiliation(s)
- Ji-Young Kim
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
| | - Ji-Hye Jung
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
| | - Soryung Jung
- Department of Life Science, Ewha Womans University, Seoul, Republic of Korea
| | - Sanghyuk Lee
- Department of Life Science, Ewha Womans University, Seoul, Republic of Korea
| | - Hyang Ah Lee
- Department of Obstetrics and Gynecology, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
| | - Yung-Taek Ouh
- Department of Obstetrics and Gynecology, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
- Department of Obstetrics and Gynecology, Ansan Hospital, Korea University College of Medicine, Gyeonggi, Republic of Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
- KW-Bio Co., Ltd, Chuncheon, Republic of Korea
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12
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Buruiană A, Gheban BA, Gheban-Roșca IA, Georgiu C, Crișan D, Crișan M. The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression. Cancers (Basel) 2024; 16:1727. [PMID: 38730679 PMCID: PMC11083853 DOI: 10.3390/cancers16091727] [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: 04/08/2024] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
The tumor microenvironment (TME), a complex assembly of cellular and extracellular matrix (ECM) components, plays a crucial role in driving tumor progression, shaping treatment responses, and influencing metastasis. This narrative review focuses on the cutaneous squamous cell carcinoma (cSCC) tumor stroma, highlighting its key constituents and their dynamic contributions. We examine how significant changes within the cSCC ECM-specifically, alterations in fibronectin, hyaluronic acid, laminins, proteoglycans, and collagens-promote cancer progression, metastasis, and drug resistance. The cellular composition of the cSCC TME is also explored, detailing the intricate interplay of cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, pericytes, adipocytes, and various immune cell populations. These diverse players modulate tumor development, angiogenesis, and immune responses. Finally, we emphasize the TME's potential as a therapeutic target. Emerging strategies discussed in this review include harnessing the immune system (adoptive cell transfer, checkpoint blockade), hindering tumor angiogenesis, disrupting CAF activity, and manipulating ECM components. These approaches underscore the vital role that deciphering TME interactions plays in advancing cSCC therapy. Further research illuminating these complex relationships will uncover new avenues for developing more effective treatments for cSCC.
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Affiliation(s)
- Alexandra Buruiană
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Bogdan-Alexandru Gheban
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Emergency Clinical County Hospital, 400347 Cluj-Napoca, Romania
| | - Ioana-Andreea Gheban-Roșca
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, 400129 Cluj-Napoca, Romania;
| | - Carmen Georgiu
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Doința Crișan
- Department of Pathology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.B.); (C.G.); (D.C.)
| | - Maria Crișan
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
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13
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Fuentes AM, Milligan K, Wiebe M, Narayan A, Lum JJ, Brolo AG, Andrews JL, Jirasek A. Stratification of tumour cell radiation response and metabolic signatures visualization with Raman spectroscopy and explainable convolutional neural network. Analyst 2024; 149:1645-1657. [PMID: 38312026 DOI: 10.1039/d3an01797d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2024]
Abstract
Reprogramming of cellular metabolism is a driving factor of tumour progression and radiation therapy resistance. Identifying biochemical signatures associated with tumour radioresistance may assist with the development of targeted treatment strategies to improve clinical outcomes. Raman spectroscopy (RS) can monitor post-irradiation biomolecular changes and signatures of radiation response in tumour cells in a label-free manner. Convolutional Neural Networks (CNN) perform feature extraction directly from data in an end-to-end learning manner, with high classification performance. Furthermore, recently developed CNN explainability techniques help visualize the critical discriminative features captured by the model. In this work, a CNN is developed to characterize tumour response to radiotherapy based on its degree of radioresistance. The model was trained to classify Raman spectra of three human tumour cell lines as radiosensitive (LNCaP) or radioresistant (MCF7, H460) over a range of treatment doses and data collection time points. Additionally, a method based on Gradient-Weighted Class Activation Mapping (Grad-CAM) was used to determine response-specific salient Raman peaks influencing the CNN predictions. The CNN effectively classified the cell spectra, with accuracy, sensitivity, specificity, and F1 score exceeding 99.8%. Grad-CAM heatmaps of H460 and MCF7 cell spectra (radioresistant) exhibited high contributions from Raman bands tentatively assigned to glycogen, amino acids, and nucleic acids. Conversely, heatmaps of LNCaP cells (radiosensitive) revealed activations at lipid and phospholipid bands. Finally, Grad-CAM variable importance scores were derived for glycogen, asparagine, and phosphatidylcholine, and we show that their trends over cell line, dose, and acquisition time agreed with previously established models. Thus, the CNN can accurately detect biomolecular differences in the Raman spectra of tumour cells of varying radiosensitivity without requiring manual feature extraction. Finally, Grad-CAM may help identify metabolic signatures associated with the observed categories, offering the potential for automated clinical tumour radiation response characterization.
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Affiliation(s)
- Alejandra M Fuentes
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada.
| | - Kirsty Milligan
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada.
| | - Mitchell Wiebe
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada.
| | - Apurva Narayan
- Department of Computer Science, Western University, London, Canada
- Department of Computer Science, The University of British Columbia Okanagan Campus, Kelowna, Canada
| | - Julian J Lum
- Department of Biochemistry and Microbiology, The University of Victoria, Victoria, Canada
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, Canada
| | - Alexandre G Brolo
- Department of Chemistry, The University of Victoria, Victoria, Canada
| | - Jeffrey L Andrews
- Department of Statistics, The University of British Columbia Okanagan Campus, Kelowna, Canada
| | - Andrew Jirasek
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada.
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Hou Z, Wu C, Tang J, Liu S, Li L. CLSPN actives Wnt/β-catenin signaling to facilitate glycolysis and cell proliferation in oral squamous cell carcinoma. Exp Cell Res 2024; 435:113935. [PMID: 38237848 DOI: 10.1016/j.yexcr.2024.113935] [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: 10/19/2023] [Revised: 01/01/2024] [Accepted: 01/15/2024] [Indexed: 02/04/2024]
Abstract
OBJECTIVE Oral squamous cell carcinoma (OSCC) is a common malignancy with a poor prognosis. This study aimed to determine the influence and underlying mechanisms of CLSPN on OSCC. METHODS CLSPN expression was tested using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting. Flow cytometry, cell counting kit, and colony formation assays were performed to determine OSCC cell apoptosis, viability, and proliferation, respectively. In OSCC cells, the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, and lactate production were determined using the corresponding kits. Changes in the protein levels of HK2, PKM2, LDHA, Wnt3a, and β-catenin were assessed using western blotting. RESULTS CLSPN expression was increased in OSCC tissues. Overexpression of CLSPN in HSC-2 cells promoted cell proliferation, increased the levels of ECAR, glucose uptake, and lactate production, and increased the protein levels of HK2, PKM2, LDHA, Wnt3a, and β-catenin, but inhibited OCR levels and apoptosis. The knockdown of CLSPN in CAL27 cells resulted in the opposite results. Moreover, the effects of CLSPN overexpression on glycolysis and OSCC cell proliferation were reversed by Wnt3a knockdown. In vivo, knockdown of CLSPN restrained tumor growth, glycolysis, and the activation of Wnt/β-catenin signaling. CONCLUSION CLSPN promoted glycolysis and OSCC cell proliferation, and reduced apoptosis, which was achieved by the activation of Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Zeyu Hou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jinru Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Shaohua Liu
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
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15
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Romo-Perez A, Domínguez-Gómez G, Chávez-Blanco AD, González-Fierro A, Correa-Basurto J, Dueñas-González A. PaSTe. Blockade of the Lipid Phenotype of Prostate Cancer as Metabolic Therapy: A Theoretical Proposal. Curr Med Chem 2024; 31:3265-3285. [PMID: 37287286 DOI: 10.2174/0929867330666230607104441] [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: 12/08/2022] [Revised: 04/10/2023] [Accepted: 05/09/2023] [Indexed: 06/09/2023]
Abstract
BACKGROUND Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO). OBJECTIVE Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-β-Ketoacyl- CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer. RESULTS Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs. CONCLUSION We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.
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Affiliation(s)
- Adriana Romo-Perez
- Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | - Alma D Chávez-Blanco
- Subdirección de Investigación Básica, Instituto Nacional de Cancerologia, Mexico City, Mexico
| | - Aurora González-Fierro
- Subdirección de Investigación Básica, Instituto Nacional de Cancerologia, Mexico City, Mexico
| | - José Correa-Basurto
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Alfonso Dueñas-González
- Subdirección de Investigación Básica, Instituto Nacional de Cancerologia, Mexico City, Mexico
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
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16
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Meng D, Ren M, Li M, Wang M, Geng W, Shang Q. Molecular mechanism of α-Hederin in tumor progression. Biomed Pharmacother 2024; 170:116097. [PMID: 38160624 DOI: 10.1016/j.biopha.2023.116097] [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: 10/18/2023] [Revised: 12/16/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024] Open
Abstract
α-Hederin is a monosaccharide pentacyclic triterpene saponin compound derived from the Chinese herb, Pulsatilla. It has garnered considerable attention for its anti-tumor, anti-inflammatory, and spasmolytic pharmacological activities. Given the rising incidence of cancer and the pronounced adverse reactions associated with chemotherapy drugs-which profoundly impact the quality of life for cancer patients-there is an immediate need for safe and effective antitumor agents. Traditional drugs and their anticancer effects have become a focal point of research in recent years. Studies indicate that α-Hederin can hinder tumor cell proliferation and impede the advancement of various cancers, including breast, lung, colorectal, and liver cancers. The principal mechanism behind its anti-tumor activity involves inhibiting tumor cell proliferation, facilitating tumor cell apoptosis, and arresting the cell cycle process. Current evidence suggests that α-Hederin can exert its anti-tumor properties through diverse mechanisms, positioning it as a promising agent in anti-tumor therapy. However, a comprehensive literature search revealed a gap in the comprehensive understanding of α-Hederin. This paper aims to review the available literature on the anti-tumor mechanisms of α-Hederin, hoping to provide valuable insights for the clinical treatment of malignant tumors and the innovation of novel anti-tumor medications.
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Affiliation(s)
- Dandan Meng
- Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Changqing District, Jinan 250355, Shangdong, China
| | - Meng Ren
- Department of Physical Education, Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Changqing District, Jinan 250355, Shangdong, China
| | - Maofeng Li
- College of Foreign Chinese, Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Changqing District, Jinan 250355, Shangdong, China
| | - Min Wang
- Experimental Center of Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Changqing District, Jinan 250355, Shangdong, China
| | - Wei Geng
- Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, No. 238, Jingshi East Road, Lixia District, Jinan 250014, China
| | - Qingxin Shang
- Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Changqing District, Jinan 250355, Shangdong, China.
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17
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Zhang F, Wang B, Zhang W, Xu Y, Zhang C, Xue X. Transcription Factor MAZ Potentiates the Upregulated NEIL3-mediated Aerobic Glycolysis, thereby Promoting Angiogenesis in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2024; 24:1235-1249. [PMID: 38347781 DOI: 10.2174/0115680096265896231226062212] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/06/2023] [Accepted: 11/17/2023] [Indexed: 09/25/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is characterized by high vascularity and notable abnormality of blood vessels, where angiogenesis is a key process in tumorigenesis and metastasis. The main functions of Nei Like DNA Glycosylase 3 (NEIL3) include DNA alcoholization repair, immune response regulation, nervous system development and function, and DNA damage signal transduction. However, the underlying mechanism of high expression NEIL3 in the development and progression of HCC and whether the absence or silencing of NEIL3 inhibits the development of cancer remain unclear. Therefore, a deeper understanding of the mechanisms by which increased NEIL3 expression promotes cancer development is needed. METHODS Expression of NEIL3 and its upstream transcription factor MAZ in HCC tumor tissues was analyzed in bioinformatics efforts, while validation was done by qRT-PCR and western blot in HCC cell lines. The migration and tube formation capacity of HUVEC cells were analyzed by Transwell and tube formation assays. Glycolytic capacity was analyzed by extracellular acidification rate, glucose uptake, and lactate production levels. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter gene assays were utilized to investigate specific interactions between MAZ and NEIL3. RESULTS NEIL3 and MAZ were substantially upregulated in HCC tissues and cells. NEIL3 was involved in modulating the glycolysis pathway, suppression of which reversed the stimulative impact of NEIL3 overexpression on migration and angiogenesis in HUVEC cells. MAZ bound to the promoter of NEIL3 to facilitate NEIL3 transcription. Silencing MAZ reduced NEIL3 expression and suppressed the glycolysis pathway, HUVEC cell migration, and angiogenesis. CONCLUSION MAZ potentiated the upregulated NEIL3-mediated glycolysis pathway and HCC angiogenesis. This study provided a rationale for the MAZ/NEIL3/glycolysis pathway as a possible option for anti-angiogenesis therapy in HCC.
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Affiliation(s)
- Fabiao Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Binfeng Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Wenlong Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Yongfu Xu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Caiming Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Xiangyang Xue
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
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Strużyńska L. Dual Implications of Nanosilver-Induced Autophagy: Nanotoxicity and Anti-Cancer Effects. Int J Mol Sci 2023; 24:15386. [PMID: 37895066 PMCID: PMC10607027 DOI: 10.3390/ijms242015386] [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: 09/30/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
In recent years, efforts have been made to identify new anti-cancer therapies. Various types of nanomaterials, including silver nanoparticles (AgNPs), are being considered as an option. In addition to its well-known antibacterial activity, AgNPs exhibit cytotoxic potential in both physiological and cancer cells by inducing stress-mediated autophagy and apoptotic cell death. A rapidly growing collection of data suggests that the proper regulation of autophagic machinery may provide an efficient tool for suppressing the development of cancer. In this light, AgNPs have emerged as a potential anti-cancer agent to support therapy of the disease. This review summarizes current data indicating the dual role of AgNP-induced autophagy and highlights factors that may influence its protective vs. its toxic potential. It also stresses that our understanding of the cellular and molecular mechanisms of autophagy machinery in cancer cells, as well as AgNP-triggered autophagy in both normal and diseased cells, remains insufficient.
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Affiliation(s)
- Lidia Strużyńska
- Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego str., 02-106 Warsaw, Poland
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Choi HK, Park SH, Lee J, Hwang JT. Review of Patents for Anticancer Agents Targeting Adenosine Monophosphate-Activated Protein Kinase. J Med Food 2023; 26:605-615. [PMID: 37590001 DOI: 10.1089/jmf.2023.k.0026] [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] [Indexed: 08/18/2023] Open
Abstract
Cancer, caused by abnormal and excessive cellular proliferation, can invade and destroy surrounding tissues and organs through the spreading of cancer cells. A general strategy for developing anticancer agents is to identify biomarkers that, if targeted, can produce a robust cytotoxic effect with minimal side effects. Cell-cycle regulators, checkpoint regulatory genes, and apoptosis-related genes are well-known biomarkers that inhibit cancer cell proliferation. Several compounds that target such biomarkers have been patented and more are being developed as novel therapies. Recent additions to this list include anticancer drugs that target signaling pathway proteins, such as 5' adenosine monophosphate-activated protein kinase (AMPK), which plays a vital role in cancer and normal cell metabolism. Herein, we have reviewed recent patents related to AMPK-targeting anticancer drugs and discussed the mechanisms of action of these drugs. We conclude that these recently published patents include several attractive compounds and methods for targeting AMPK. Further research and clinical trials are required to elucidate the comprehensive role of AMPK in cancer cell metabolism, identify its associated signal transduction systems, and develop novel activators that may find applications in cancer therapy. Clinical Trial Registration number: NCT01904123.
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Affiliation(s)
- Hyo-Kyoung Choi
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
| | - Soo-Hyun Park
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
| | - Jangho Lee
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
| | - Jin-Taek Hwang
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
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Ganjoo S, Gupta P, Corbali HI, Nanez S, Riad TS, Duong LK, Barsoumian HB, Masrorpour F, Jiang H, Welsh JW, Cortez MA. The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy. Front Immunol 2023; 14:1172931. [PMID: 37180129 PMCID: PMC10169689 DOI: 10.3389/fimmu.2023.1172931] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/13/2023] [Indexed: 05/15/2023] Open
Abstract
Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.
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Affiliation(s)
- Shonik Ganjoo
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Priti Gupta
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Halil Ibrahim Corbali
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Medical Pharmacology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Türkiye
| | - Selene Nanez
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Thomas S. Riad
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Lisa K. Duong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hampartsoum B. Barsoumian
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Fatemeh Masrorpour
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hong Jiang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - James W. Welsh
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maria Angelica Cortez
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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21
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Nickel GA, Diehl KL. Chemical Biology Approaches to Identify and Profile Interactors of Chromatin Modifications. ACS Chem Biol 2023; 18:1014-1026. [PMID: 35238546 PMCID: PMC9440160 DOI: 10.1021/acschembio.1c00794] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In eukaryotes, DNA is packaged with histone proteins in a complex known as chromatin. Both the DNA and histone components of chromatin can be chemically modified in a wide variety of ways, resulting in a complex landscape often referred to as the "epigenetic code". These modifications are recognized by effector proteins that remodel chromatin and modulate transcription, translation, and repair of the underlying DNA. In this Review, we examine the development of methods for characterizing proteins that interact with these histone and DNA modifications. "Mark first" approaches utilize chemical, peptide, nucleosome, or oligonucleotide probes to discover interactors of a specific modification. "Reader first" approaches employ arrays of peptides, nucleosomes, or oligonucleotides to profile the binding preferences of interactors. These complementary strategies have greatly enhanced our understanding of how chromatin modifications effect changes in genomic regulation, bringing us ever closer to deciphering this complex language.
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Affiliation(s)
- Garrison A. Nickel
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States
| | - Katharine L. Diehl
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States
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22
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Fuentes AM, Narayan A, Milligan K, Lum JJ, Brolo AG, Andrews JL, Jirasek A. Raman spectroscopy and convolutional neural networks for monitoring biochemical radiation response in breast tumour xenografts. Sci Rep 2023; 13:1530. [PMID: 36707535 PMCID: PMC9883395 DOI: 10.1038/s41598-023-28479-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 01/19/2023] [Indexed: 01/29/2023] Open
Abstract
Tumour cells exhibit altered metabolic pathways that lead to radiation resistance and disease progression. Raman spectroscopy (RS) is a label-free optical modality that can monitor post-irradiation biomolecular signatures in tumour cells and tissues. Convolutional Neural Networks (CNN) perform automated feature extraction directly from data, with classification accuracy exceeding that of traditional machine learning, in cases where data is abundant and feature extraction is challenging. We are interested in developing a CNN-based predictive model to characterize clinical tumour response to radiation therapy based on their degree of radiosensitivity or radioresistance. In this work, a CNN architecture is built for identifying post-irradiation spectral changes in Raman spectra of tumour tissue. The model was trained to classify irradiated versus non-irradiated tissue using Raman spectra of breast tumour xenografts. The CNN effectively classified the tissue spectra, with accuracies exceeding 92.1% for data collected 3 days post-irradiation, and 85.0% at day 1 post-irradiation. Furthermore, the CNN was evaluated using a leave-one-out- (mouse, section or Raman map) validation approach to investigate its generalization to new test subjects. The CNN retained good predictive accuracy (average accuracies 83.7%, 91.4%, and 92.7%, respectively) when little to no information for a specific subject was given during training. Finally, the classification performance of the CNN was compared to that of a previously developed model based on group and basis restricted non-negative matrix factorization and random forest (GBR-NMF-RF) classification. We found that CNN yielded higher classification accuracy, sensitivity, and specificity in mice assessed 3 days post-irradiation, as compared with the GBR-NMF-RF approach. Overall, the CNN can detect biochemical spectral changes in tumour tissue at an early time point following irradiation, without the need for previous manual feature extraction. This study lays the foundation for developing a predictive framework for patient radiation response monitoring.
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Affiliation(s)
- Alejandra M Fuentes
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada
| | - Apurva Narayan
- Department of Computer Science, Western University, London, Canada
- Department of Computer Science, The University of British Columbia Okanagan Campus, Kelowna, Canada
| | - Kirsty Milligan
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada
| | - Julian J Lum
- Department of Biochemistry and Microbiology, The University of Victoria, Victoria, Canada
| | - Alex G Brolo
- Department of Chemistry, The University of Victoria, Victoria, Canada
| | - Jeffrey L Andrews
- Department of Statistics, The University of British Columbia Okanagan Campus, Kelowna, Canada
| | - Andrew Jirasek
- Department of Physics, The University of British Columbia Okanagan Campus, Kelowna, Canada.
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23
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IK Ca channels control breast cancer metabolism including AMPK-driven autophagy. Cell Death Dis 2022; 13:902. [PMID: 36302750 PMCID: PMC9613901 DOI: 10.1038/s41419-022-05329-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/28/2022] [Accepted: 10/07/2022] [Indexed: 11/30/2022]
Abstract
Ca2+-activated K+ channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors. Loss of IK altered the sub-/cellular K+- and Ca2+- homeostasis and mitochondrial membrane potential, ultimately resulting in reduced ATP-production and metabolic activity. Consequently, we find that BC cells lacking IK upregulate AMP-activated protein kinase activity to induce autophagy compensating the glycolytic and mitochondrial energy shortage. Our results emphasize that IK by modulating cellular Ca2+- and K+-dynamics contributes to the remodeling of metabolic pathways in cancer. Thus, targeting IK channel might disturb the metabolic activity of BC cells and reduce malignancy.
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24
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Novel Thieno [2,3-b]pyridine Anticancer Compound Lowers Cancer Stem Cell Fraction Inducing Shift of Lipid to Glucose Metabolism. Int J Mol Sci 2022; 23:ijms231911457. [PMID: 36232754 PMCID: PMC9569594 DOI: 10.3390/ijms231911457] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 11/19/2022] Open
Abstract
Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC–MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.
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25
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Zhu W, Wang J, Liu X, Xu Y, Zhai R, Zhang J, Wang M, Wang M, Liu L. lncRNA CYTOR promotes aberrant glycolysis and mitochondrial respiration via HNRNPC-mediated ZEB1 stabilization in oral squamous cell carcinoma. Cell Death Dis 2022; 13:703. [PMID: 35963855 PMCID: PMC9376070 DOI: 10.1038/s41419-022-05157-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 01/21/2023]
Abstract
Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral and maxillofacial region, severely affects human health. However, current treatments for OSCC commonly show only a ~60% 5-year survival rate of patients with distant metastases, indicating an urgent need for targeted treatments for patients with advanced metastases. Here, we report a survival-related long non-coding RNA, CYTOR, which is highly expressed in the lesions of oral cancer patients. We found that CYTOR can promote both migration and invasion in oral cancer cells as well as the epithelial-mesenchymal transition (EMT). RNA-sequencing of CYTOR-knockdown oral cancer cells revealed that CYTOR can regulate mitochondrial respiration and RNA splicing. Mechanistically, we found that nuclear-localized CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC. By synthesizing CYTOR-targeting small interfering RNAs (siRNAs) encapsulated in Nanoscale Metal Organic Frameworks (NMOFs), we demonstrate the targeted suppression of CYTOR to inhibit invasion and metastasis of oral cancer cells in a nude mouse model. Cumulatively, this study reveals the potential role of the CYTOR-HNRNPC-ZEB1 axis in regulating mitochondrial metabolism and glycolysis of oral cancer cells, and illustrates the effective use of lncRNA targeting in anti-metastatic cancer therapies.
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Affiliation(s)
- Weiwen Zhu
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Jie Wang
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Xiang Liu
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Yanbin Xu
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Rundong Zhai
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Jiayi Zhang
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Mengqi Wang
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Mengyao Wang
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Laikui Liu
- grid.89957.3a0000 0000 9255 8984Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China ,grid.89957.3a0000 0000 9255 8984Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Jiangsu, China ,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
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26
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Su H, Bak EJ, Kim A, Tissera K, Cha JH, Jang S. Helicobacter pylori-mediated gastric pathogenesis is attenuated by treatment of 2-deoxyglucose and metformin. J Microbiol 2022; 60:849-858. [DOI: 10.1007/s12275-022-2130-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 11/30/2022]
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Xiao J, Wang X, Liu Y, Liu X, Yi J, Hu J. Lactate Metabolism-Associated lncRNA Pairs: A Prognostic Signature to Reveal the Immunological Landscape and Mediate Therapeutic Response in Patients With Colon Adenocarcinoma. Front Immunol 2022; 13:881359. [PMID: 35911752 PMCID: PMC9328180 DOI: 10.3389/fimmu.2022.881359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 06/16/2022] [Indexed: 11/30/2022] Open
Abstract
Background Lactate metabolism is critically involved in the tumor microenvironment (TME), as well as cancer progression. It is important to note, however, that lactate metabolism-related long non-coding RNAs (laRlncRNAs) remain incredibly understudied in colon adenocarcinoma (COAD). Methods A gene expression profile was obtained from the Cancer Genome Atlas (TCGA) database to identify laRlncRNA expression in COAD patients. A risk signature with prognostic value was identified from TCGA and Gene Expression Omnibus (GEO) cohort based on laRlncRNA pairs by the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) and functional experiments were carried out to verify the expression of laRlncRNAs in COAD. The relationship of laRlncRNA pairs with immune landscape as well as the sensitivity of different therapies was explored. Results In total, 2378 laRlncRNAs were identified, 1,120 pairs of which were studied to determine their prognostic validity, followed by a risk signature established based on the screened 5 laRlncRNA pairs. The laRlncRNA pairs-based signature provided a better overall survival (OS) prediction than other published signatures and functioned as a prognostic marker for COAD patients. According to the calculated optimal cut-off point, patients were divided into high- and low-risk groups. The OS of COAD patients in the high-risk group were significantly shorter than that of those in the low-risk group (P=4.252e-14 in the TCGA cohort and P=2.865-02 in the GEO cohort). Furthermore, it remained an effective predictor of survival in strata of gender, age, TNM stage, and its significance persisted after univariate and multivariate Cox regressions. Additionally, the risk signature was significantly correlated with immune cells infiltration, tumor mutation burden (TMB), microsatellite instability (MSI) as well as immunotherapeutic efficacy and chemotherapy sensitivity. Finally, one of the laRlncRNA, LINC01315, promotes proliferation and migration capacities of colon cancer cells. Conclusion The newly identified laRlncRNAs pairs-based signature exhibits potential effects in predicting prognosis, deciphering patients’ immune landscape, and mediating sensitivity to immunotherapy and chemotherapy. Findings in our study may provide evidence for the role of laRlncRNAs pairs as novel prognostic biomarkers and potentially individualized therapy targets for COAD patients.
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Affiliation(s)
- Junbo Xiao
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaotong Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yajun Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jun Yi
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- *Correspondence: Jun Yi, ; Jiuye Hu,
| | - Jiuye Hu
- Department of Gastroenterology, Affiliated Hospital of Xiangnan University, Chenzhou, China
- *Correspondence: Jun Yi, ; Jiuye Hu,
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Du Z, Li T, Huang J, Chen Y, Chen C. Arginase: Mechanisms and Clinical Application in Hematologic Malignancy. Front Oncol 2022; 12:905893. [PMID: 35814439 PMCID: PMC9260017 DOI: 10.3389/fonc.2022.905893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Compared to normal tissues and cells, the metabolic patterns of tumor illnesses are more complex, and there are hallmarks of metabolic reprogramming in energy metabolism, lipid metabolism, and amino acid metabolism. When tumor cells are in a state of fast growth, they are susceptible to food shortage, resulting in growth suppression. Using this metabolic sensitivity of tumor cells to construct amino acid consumption therapy does not harm the function of normal cells, which is the focus of metabolic therapy research at the moment. As a non-essential amino acid, arginine is involved in numerous crucial biological processes, including the signaling system, cell proliferation, and material metabolism. Rapidly dividing tumor cells are more likely to be deficient in arginine; hence, utilizing arginase to consume arginine can suppress tumor growth. Due to the absence of arginine succinate synthase, arginine succinate lyase, and ornithine carbamoyl transferase in some blood tumors, arginases may be employed to treat blood tumors. By investigating the mechanism of arginase treatment and the mechanism of drug resistance in greater depth, arginase treatment becomes more successful in hematological cancers and a new anti-cancer agent in clinical practice.
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Affiliation(s)
- Zefan Du
- Department of Pediatrics, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Tianwen Li
- Department of Pediatrics, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Junbin Huang
- Department of Pediatrics, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Yun Chen
- Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- *Correspondence: Yun Chen, ; Chun Chen,
| | - Chun Chen
- Department of Pediatrics, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yun Chen, ; Chun Chen,
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Rado M, Fisher D. The Paracrine Effect of Hypoxic and Normoxic Cancer Secretion on the Proliferation of Brain Endothelial Cells (bEnd.3). Cells 2022; 11:cells11071197. [PMID: 35406760 PMCID: PMC8997846 DOI: 10.3390/cells11071197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 12/04/2022] Open
Abstract
Background: This study aimed to investigate the disruption of cell cycle phases of bEnd.3 cells exposed to cancer paracrine secretion. Cancer cells have been reported to use the secretion of paracrine factors to compromise the endothelial barrier to prepare for their passage into the parenchyma. As cancer cells are known to act differently under conditions of hypoxia, we investigated how conditional media (CM) derived from breast and glioblastoma cells incubated under conditions of normoxia and hypoxia would affect proliferation of brain endothelial cells (bEnd.3). Methods: Brain endothelial cells (bEnd.3) were cultivated with normoxic and hypoxic CM generated from breast cancer MCF7 cells and glioblastoma U-87 cells. Cell proliferation was evaluated using the trypan blue exclusion assay and phases of the cell cycle were evaluated using flow cytometry. Results: bEnd.3 proliferations was suppressed more aggressively with hypoxic CM after 72 and 96 h; cell cycle analysis showed that paracrine treatment tended to prevent BECs from entering the G2 phase, thus suppressing cell division. Conclusions: MCF7 and U-87 cells induce suppressed proliferation of BECs deferentially under hypoxia by blocking cell cycle progression to the G2 phase.
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Li Q, Chen Q, Yang X, Zhang Y, Lv L, Zhang Z, Zeng S, Lv J, Liu S, Fu B. Cocktail strategy based on a dual function nanoparticle and immune activator for effective tumor suppressive. J Nanobiotechnology 2022; 20:84. [PMID: 35177088 PMCID: PMC8851817 DOI: 10.1186/s12951-022-01241-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/02/2022] [Indexed: 11/26/2022] Open
Abstract
Background Immune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration. Methods The particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments. Results Here, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1–6 cells. We found that the drug-treated Hepa1–6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer. Conclusion Our results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01241-y.
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Affiliation(s)
- Qian Li
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
| | - Qiubing Chen
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xue Yang
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuelan Zhang
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Linyue Lv
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhuyou Zhang
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shaowei Zeng
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiaxi Lv
- Department of Clinical Medicine, Fourth Clinical Medical College, Capital Medical University, Beijing, People's Republic of China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
| | - Bishi Fu
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China. .,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. .,Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
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Resendiz-Acevedo K, García-Aguilera ME, Esturau-Escofet N, Ruiz-Azuara L. 1H -NMR Metabolomics Study of the Effect of Cisplatin and Casiopeina IIgly on MDA-MB-231 Breast Tumor Cells. Front Mol Biosci 2021; 8:742859. [PMID: 34926572 PMCID: PMC8671756 DOI: 10.3389/fmolb.2021.742859] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/02/2021] [Indexed: 01/06/2023] Open
Abstract
The knowledge of the metabolic processes of designed metallodrugs for cancer treatment is an area that has been not profoundly studied. Casiopeina IIgly (CasIIgly), which belongs to the Casiopeínas® family, is a copper (II) coordination compound that has shown good biological activity against several cancer cells, low toxicity in normal cells, and antineoplastic activity in in vivo murine and xenografted models. In this work we employed a triple-negative highly metastatic breast carcinoma line (MDA-MB-231), which is one of the cancer types with a great mortality index, for 1H-NMR metabolomic analysis using cisplatin and CasIIgly, in order to quantify the effect of metallodrugs in the metabolic profile of this cell tumor line as a consequence of treatment at different times. Our findings indicate that cisplatin mainly contributes to phospholipid biosynthesis while CasIIgly affects processes such as carbohydrates and nucleotides metabolism. Also, we observed that CasIIgly treatment has an important and fast effect over MDA-MB-231 cell metabolism, which makes it a good alternative for treatment in this type of cancer.
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Affiliation(s)
| | | | - Nuria Esturau-Escofet
- Instituto de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Lena Ruiz-Azuara
- Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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Fang C, Liu Y, Chen L, Luo Y, Cui Y, Zhang N, Liu P, Zhou M, Xie Y. α-Hederin inhibits the growth of lung cancer A549 cells in vitro and in vivo by decreasing SIRT6 dependent glycolysis. PHARMACEUTICAL BIOLOGY 2021; 59:11-20. [PMID: 33356727 PMCID: PMC7782159 DOI: 10.1080/13880209.2020.1862250] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
CONTEXT α-Hederin, a potent bioactive compound of Pulsatilla chinensis (Bunge) Regel (Ranunculaceae), has many pharmacological uses, but its effect on cancer cell metabolism is still unclear. OBJECTIVE To elucidate the role of α-hederin in the glucose metabolism of lung cancer cells. MATERIALS AND METHODS Cell Counting Kit 8 and colony formation assays were employed to assess the antiproliferative effects of α-hederin. Glucose uptake, ATP generation, and lactate production were measured. Glycolysis-related proteins were detected using western blotting, and a sirtuin 6 (SIRT6) inhibitor was used to verify A549 cell proliferation. Sixty male BALB/c nude mice were divided into normal control, 5-FU (25 mg/kg), and α-hederin (5 and 10 mg/kg) groups to assess the antitumor effect for 32 days. Glycolysis-related protein expression was evaluated using immunohistochemical analysis. RESULTS α-Hederin inhibited A549 (IC50 = 13.75 μM), NCI-H460 (IC50 = 17.57 μM), and NCI-H292 (IC50 = 18.04 μM) proliferation; inhibited glucose uptake and ATP generation; and reduced lactate production. Furthermore, α-hederin (10 and 15 μM) markedly inhibited hexokinase 2, glucose transporter 1, pyruvate kinase M2, lactate dehydrogenase A, monocarboxylate transporter, c-Myc, hypoxia-inducible factor-1α, and activated SIRT6 protein expression. Using a SIRT6 inhibitor, we demonstrated that α-hederin inhibits glycolysis by activating SIRT6. A tumour xenograft mouse model of lung cancer confirmed that α-hederin (5 and 10 mg/kg) inhibits lung cancer growth by inhibiting glycolysis in vivo. DISCUSSION AND CONCLUSIONS α-Hederin inhibits A549 cell growth by inhibiting SIRT6-dependent glycolysis. α-Hederin might serve as a potential agent to suppress cancer.
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Affiliation(s)
- Cong Fang
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yahui Liu
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Lanying Chen
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- CONTACT Lanying Chen National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yingying Luo
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yaru Cui
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Ni Zhang
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Peng Liu
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Mengjing Zhou
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yongyan Xie
- College of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
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Tan TCY, Mahbub SB, Campbell JM, Habibalahi A, Campugan CA, Rose RD, Chow DJX, Mustafa S, Goldys EM, Dunning KR. Non-invasive, label-free optical analysis to detect aneuploidy within the inner cell mass of the preimplantation embryo. Hum Reprod 2021; 37:14-29. [PMID: 34741175 DOI: 10.1093/humrep/deab233] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 09/28/2021] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION Can label-free, non-invasive optical imaging by hyperspectral autofluorescence microscopy discern between euploid and aneuploid cells within the inner cell mass (ICM) of the mouse preimplantation embryo? SUMMARY ANSWER Hyperspectral autofluorescence microscopy enables discrimination between euploid and aneuploid ICM in mouse embryos. WHAT IS KNOWN ALREADY Euploid/aneuploid mosaicism affects up to 17.3% of human blastocyst embryos with trophectoderm biopsy or spent media currently utilized to diagnose aneuploidy and mosaicism in clinical in vitro fertilization. Based on their design, these approaches will fail to diagnose the presence or proportion of aneuploid cells within the foetal lineage ICM of some blastocyst embryos. STUDY DESIGN, SIZE, DURATION The impact of aneuploidy on cellular autofluorescence and metabolism of primary human fibroblast cells and mouse embryos was assessed using a fluorescence microscope adapted for imaging with multiple spectral channels (hyperspectral imaging). Primary human fibroblast cells with known ploidy were subjected to hyperspectral imaging to record native cell fluorescence (4-6 independent replicates, euploid n = 467; aneuploid n = 969). For mouse embryos, blastomeres from the eight-cell stage (five independent replicates: control n = 39; reversine n = 44) and chimeric blastocysts (eight independent replicates: control n = 34; reversine n = 34; 1:1 (control:reversine) n = 30 and 1:3 (control:reversine) n = 37) were utilized for hyperspectral imaging. The ICM from control and reversine-treated embryos were mechanically dissected and their karyotype confirmed by whole genome sequencing (n = 13 euploid and n = 9 aneuploid). PARTICIPANTS/MATERIALS, SETTING, METHODS Two models were employed: (i) primary human fibroblasts with known karyotype and (ii) a mouse model of embryo aneuploidy where mouse embryos were treated with reversine, a reversible spindle assembly checkpoint inhibitor, during the four- to eight-cell division. Individual blastomeres were dissociated from control and reversine-treated eight-cell embryos and either imaged directly or used to generate chimeric blastocysts with differing ratios of control:reversine-treated cells. Individual blastomeres and embryos were interrogated by hyperspectral imaging. Changes in cellular metabolism were determined by quantification of metabolic co-factors (inferred from their autofluorescence signature): NAD(P)H and flavins with the subsequent calculation of the optical redox ratio (ORR: flavins/[NAD(P)H + flavins]). Autofluorescence signals obtained from hyperspectral imaging were examined mathematically to extract features from each cell/blastomere/ICM. This was used to discriminate between different cell populations. MAIN RESULTS AND THE ROLE OF CHANCE An increase in the relative abundance of NAD(P)H and decrease in flavins led to a significant reduction in the ORR for aneuploid cells in primary human fibroblasts and reversine-treated mouse blastomeres (P < 0.05). Mathematical analysis of endogenous cell autofluorescence achieved separation between (i) euploid and aneuploid primary human fibroblast cells, (ii) control and reversine-treated mouse blastomeres cells, (iii) control and reversine-treated chimeric blastocysts, (iv) 1:1 and 1:3 chimeric blastocysts and (v) confirmed euploid and aneuploid ICM from mouse blastocysts. The accuracy of these separations was supported by receiver operating characteristic curves with areas under the curve of 0.97, 0.99, 0.87, 0.88 and 0.93, respectively. We believe that the role of chance is low as mathematical features separated euploid from aneuploid in both human fibroblasts and ICM of mouse blastocysts. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Although we were able to discriminate between euploid and aneuploid ICM in mouse blastocysts, confirmation of this approach in human embryos is required. While we show this approach is safe in mouse, further validation is required in large animal species prior to implementation in a clinical setting. WIDER IMPLICATIONS OF THE FINDINGS We have developed an original, accurate and non-invasive optical approach to assess aneuploidy within the ICM of mouse embryos in the absence of fluorescent tags. Hyperspectral autofluorescence imaging was able to discriminate between euploid and aneuploid human fibroblast and mouse blastocysts (ICM). This approach may potentially lead to a new diagnostic for embryo analysis. STUDY FUNDING/COMPETING INTEREST(S) K.R.D. is supported by a Mid-Career Fellowship from the Hospital Research Foundation (C-MCF-58-2019). This study was funded by the Australian Research Council Centre of Excellence for Nanoscale Biophotonics (CE140100003) and the National Health and Medical Research Council (APP2003786). The authors declare that there is no conflict of interest.
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Affiliation(s)
- Tiffany C Y Tan
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, The University of Adelaide, Adelaide, SA, Australia
| | - Saabah B Mahbub
- The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Kensington, NSW, Australia.,Australian Research Council Centre of Excellence Centre for Nanoscale Biophotonics, University of New South Wales, Kensington, NSW, Australia
| | - Jared M Campbell
- The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Kensington, NSW, Australia.,Australian Research Council Centre of Excellence Centre for Nanoscale Biophotonics, University of New South Wales, Kensington, NSW, Australia
| | - Abbas Habibalahi
- The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Kensington, NSW, Australia.,Australian Research Council Centre of Excellence Centre for Nanoscale Biophotonics, University of New South Wales, Kensington, NSW, Australia
| | - Carl A Campugan
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, The University of Adelaide, Adelaide, SA, Australia
| | - Ryan D Rose
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.,Fertility SA, St. Andrews Hospital, Adelaide, SA, Australia
| | - Darren J X Chow
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, The University of Adelaide, Adelaide, SA, Australia
| | - Sanam Mustafa
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, The University of Adelaide, Adelaide, SA, Australia
| | - Ewa M Goldys
- The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Kensington, NSW, Australia.,Australian Research Council Centre of Excellence Centre for Nanoscale Biophotonics, University of New South Wales, Kensington, NSW, Australia
| | - Kylie R Dunning
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, The University of Adelaide, Adelaide, SA, Australia
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Bitorina AV, Oligschlaeger Y, Ding L, Yadati T, Westheim A, Houben T, Vaes RDW, Olde Damink SWM, Theys J, Shiri-Sverdlov R. OxLDL as an Inducer of a Metabolic Shift in Cancer Cells. J Cancer 2021; 12:5817-5824. [PMID: 34475995 PMCID: PMC8408103 DOI: 10.7150/jca.56307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 06/24/2021] [Indexed: 01/01/2023] Open
Abstract
Recent evidence established a link between disturbed lipid metabolism and increased risk for cancer. One of the most prominent features related to disturbed lipid metabolism is an increased production of oxidized low-density-lipoproteins (oxLDL), which results from elevated oxidative stress. OxLDL is known to have detrimental effects on healthy cells and plays a primary role in diseases related to the metabolic syndrome. Nevertheless, so far, the exact role of oxLDL in cancer cell metabolism is not yet known. To examine changes in metabolic profile induced by oxLDL, pancreatic KLM-1 cells were treated with oxLDL in a concentration- (25 or 50 µg/ml) and/or time-dependent (4 hr or 8 hr) manner and the impact of oxLDL on oxygen consumption rates (OCR) as well as extracellular acidification rates (ECAR) was analyzed using Seahorse technology. Subsequently, to establish the link between oxLDL and glycolysis, stabilization of the master regulator hypoxia-inducible factor 1-alpha (HIF-1α) was measured by means of Western blot. Furthermore, autophagic responses were assessed by measuring protein levels of the autophagosomal marker LC3B-II. Finally, the therapeutic potential of natural anti-oxLDL IgM antibodies in reversing these effects was tested. Incubation of KLM-1 cells with oxLDL shifted the energy balance towards a more glycolytic phenotype, which is an important hallmark of cancer cells. These data were supported by measurement of increased oxLDL-mediated HIF-1α stabilization. In line, oxLDL incubation also increased the levels of LC3B-II, suggesting an elevated autophagic response. Importantly, antibodies against oxLDL were able to reverse these oxLDL-mediated metabolic effects. Our data provides a novel proof-of-concept that oxLDL induces a shift in energy balance. These data not only support a role for oxLDL in the progression of cancer but also suggest the possibility of targeting oxLDL as a therapeutic option in cancer.
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Affiliation(s)
- Albert V Bitorina
- Department of Molecular Genetics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Yvonne Oligschlaeger
- Department of Molecular Genetics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Lingling Ding
- Department of Molecular Genetics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Tulasi Yadati
- Department of Molecular Genetics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Annemarie Westheim
- Department of Precision Medicine, School for Oncology & Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Tom Houben
- Department of Molecular Genetics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Rianne D W Vaes
- Department of Surgery, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Steven W M Olde Damink
- Department of Surgery, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Jan Theys
- Department of Precision Medicine, School for Oncology & Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Ronit Shiri-Sverdlov
- Department of Molecular Genetics, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
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Chandel V, Kumar D. Targeting Signalling Cross-Talk between Cancer Cells and Cancer-Associated Fibroblast through Monocarboxylate Transporters in Head and Neck Cancer. Anticancer Agents Med Chem 2021; 21:1369-1378. [PMID: 32698754 DOI: 10.2174/1871520620666200721135230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 11/22/2022]
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive malignancy affecting more than 600,000 cases worldwide annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic, with up to 80% fibroblasts. It has been reported that Cancer-Associated Fibroblasts (CAFs) facilitate HNSCC progression. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in Lactic Acid (LA) production. Earlier, it has been reported that HNSCC tumors exhibit high LA levels that correlate with reduced survival. It has been reported that the activation of the receptor tyrosine kinase, c- MET, by CAF-secreted Hepatocyte Growth Factor (HGF) is a major contributing event in the progression of HNSCC. In nasopharyngeal carcinoma, c-MET inhibition downregulates the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) and NADPH production resulting in apoptosis. Previously, it was demonstrated that HNSCC tumor cells are highly glycolytic. Further, CAFs show a higher capacity to utilize LA as a carbon source to fuel mitochondrial respiration than HNSCC. Earlier, we have reported that in admixed cultures, both cell types increase the expression of Monocarboxylate Transporters (MCTs) for a bidirectional LA transporter. Consequently, MCTs play an important role in signalling cross-talk between cancer cells and cancer associate fibroblast in head and neck cancer, and targeting MCTs would lead to the development of a potential therapeutic approach for head and neck cancer. In this review, we focus on the regulation of MCTs in head and neck cancer through signalling cross-talk between cancer cells and cancer-associated fibroblasts, and targeting this signalling cross talk would lead to the development of a potential therapeutic approach for head and neck cancer.
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Affiliation(s)
- Vaishali Chandel
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida-201313, (UP), India
| | - Dhruv Kumar
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida-201313, (UP), India
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36
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Byeon SK, Madugundu AK, Jain AP, Bhat FA, Jung JH, Renuse S, Darrow J, Bakker A, Albert M, Moghekar A, Pandey A. Cerebrospinal fluid lipidomics for biomarkers of Alzheimer's disease. Mol Omics 2021; 17:454-463. [PMID: 34125126 PMCID: PMC8210464 DOI: 10.1039/d0mo00186d] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia and is associated with serious neurologic sequelae resulting from neurodegenerative changes. Identification of markers of early-stage AD could be important for designing strategies to arrest the progression of the disease. The brain is rich in lipids because they are crucial for signal transduction and anchoring of membrane proteins. Cerebrospinal fluid (CSF) is an excellent specimen for studying the metabolism of lipids in AD because it can reflect changes occurring in the brain. We aimed to identify CSF lipidomic alterations associated with AD, using untargeted lipidomics, carried out in positive and negative ion modes. We found CSF lipids that were significantly altered in AD cases. In addition, comparison of CSF lipid profiles between persons with mild cognitive impairment (MCI) and AD showed a strong positive correlation between the lipidomes of the MCI and AD groups. The novel lipid biomarkers identified in this study are excellent candidates for validation in a larger set of patient samples and as predictive biomarkers of AD through future longitudinal studies. Once validated, the lipid biomarkers could lead to early detection, disease monitoring and the ability to measure the efficacy of potential therapeutic interventions in AD.
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Affiliation(s)
- Seul Kee Byeon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55902, USA.
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37
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Babak MV, Chong KR, Rapta P, Zannikou M, Tang HM, Reichert L, Chang MR, Kushnarev V, Heffeter P, Meier‐Menches SM, Lim ZC, Yap JY, Casini A, Balyasnikova IV, Ang WH. Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202102266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Maria V. Babak
- Drug Discovery Lab Department of Chemistry City University of Hong Kong 83 Tat Chee Avenue 999077 Hong Kong SAR P. R. China
| | - Kai Ren Chong
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
| | - Peter Rapta
- Institute of Physical Chemistry and Chemistry Physics Slovak Technical University of Technology Radlinského 9 82137 Bratislava Slovak Republic
| | - Markella Zannikou
- Department of Neurological Surgery The Feinberg School of Medicine Northwestern University Chicago IL 60611 USA
| | - Hui Min Tang
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
| | - Lisa Reichert
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
| | - Meng Rui Chang
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
| | - Vladimir Kushnarev
- FSBI “National Medical Research Center of Oncology, named after N.N Petrov” Ministry of Healthcare of the Russian Federation 68 Leningradskaya Street, Pesochny 197758 St Petersburg Russian Federation
| | - Petra Heffeter
- Institute of Cancer Research and Comprehensive Cancer Center Department of Medicine I Medical University of Vienna Borschkegasse 8a 1090 Vienna Austria
| | | | - Zhi Chiaw Lim
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
| | - Jian Yu Yap
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
| | - Angela Casini
- Department of Chemistry Technical University of Munich Lichtenbergstr. 4 85748 Garching, München Germany
| | - Irina V. Balyasnikova
- Department of Neurological Surgery The Feinberg School of Medicine Northwestern University Chicago IL 60611 USA
| | - Wee Han Ang
- Department of Chemistry National University of Singapore 3 Science Drive 2 117543 Singapore Singapore
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38
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Babak MV, Chong KR, Rapta P, Zannikou M, Tang HM, Reichert L, Chang MR, Kushnarev V, Heffeter P, Meier-Menches SM, Lim ZC, Yap JY, Casini A, Balyasnikova IV, Ang WH. Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs. Angew Chem Int Ed Engl 2021; 60:13405-13413. [PMID: 33755286 DOI: 10.1002/anie.202102266] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Indexed: 12/19/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.
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Affiliation(s)
- Maria V Babak
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, 999077, Hong Kong SAR, P. R. China
| | - Kai Ren Chong
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
| | - Peter Rapta
- Institute of Physical Chemistry and Chemistry Physics, Slovak Technical University of Technology, Radlinského 9, 82137, Bratislava, Slovak Republic
| | - Markella Zannikou
- Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Hui Min Tang
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
| | - Lisa Reichert
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
| | - Meng Rui Chang
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
| | - Vladimir Kushnarev
- FSBI "National Medical Research Center of Oncology, named after N.N Petrov", Ministry of Healthcare of the Russian Federation, 68 Leningradskaya Street, Pesochny, 197758, St Petersburg, Russian Federation
| | - Petra Heffeter
- Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria
| | - Samuel M Meier-Menches
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Zhi Chiaw Lim
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
| | - Jian Yu Yap
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
| | - Angela Casini
- Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, München, Germany
| | - Irina V Balyasnikova
- Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Wee Han Ang
- Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore
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Badodi S, Pomella N, Zhang X, Rosser G, Whittingham J, Niklison-Chirou MV, Lim YM, Brandner S, Morrison G, Pollard SM, Bennett CD, Clifford SC, Peet A, Basson MA, Marino S. Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. Nat Commun 2021; 12:2148. [PMID: 33846320 PMCID: PMC8042111 DOI: 10.1038/s41467-021-22379-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022] Open
Abstract
Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.
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Affiliation(s)
- Sara Badodi
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Nicola Pomella
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Xinyu Zhang
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gabriel Rosser
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - John Whittingham
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
| | - Maria Victoria Niklison-Chirou
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath, UK
| | - Yau Mun Lim
- UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
| | - Sebastian Brandner
- UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
| | - Gillian Morrison
- Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Steven M Pollard
- Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Christopher D Bennett
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Birmingham Women and Children's Hospital, Birmingham, UK
| | - Steven C Clifford
- Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle upon Tyne, UK
| | - Andrew Peet
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Birmingham Women and Children's Hospital, Birmingham, UK
| | - M Albert Basson
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
- MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Silvia Marino
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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40
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Kuspriyanti NP, Ariyanto EF, Syamsunarno MRAA. Role of Warburg Effect in Cardiovascular Diseases: A Potential Treatment Option. Open Cardiovasc Med J 2021. [DOI: 10.2174/1874192402115010006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background:
Under normal conditions, the heart obtains ATP through the oxidation of fatty acids, glucose, and ketones. While fatty acids are the main source of energy in the heart, under certain conditions, the main source of energy shifts to glucose where pyruvate converts into lactate, to meet the energy demand. The Warburg effect is the energy shift from oxidative phosphorylation to glycolysis in the presence of oxygen. This effect is observed in tumors as well as in diseases, including cardiovascular diseases. If glycolysis is more dominant than glucose oxidation, the two pathways uncouple, contributing to the severity of the heart condition. Recently, several studies have documented changes in metabolism in several cardiovascular diseases; however, the specific mechanisms remain unclear.
Methods:
This literature review was conducted by an electronic database of Pub Med, Google Scholar, and Scopus published until 2020. Relevant papers are selected based on inclusion and exclusion criteria.
Results:
A total of 162 potentially relevant articles after the title and abstract screening were screened for full-text. Finally, 135 papers were included for the review article.
Discussion:
This review discusses the effects of alterations in glucose metabolism, particularly the Warburg effect, on cardiovascular diseases, including heart failure, atrial fibrillation, and cardiac hypertrophy.
Conclusion:
Reversing the Warburg effect could become a potential treatment option for cardiovascular diseases.
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41
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Milligan K, Deng X, Shreeves P, Ali-Adeeb R, Matthews Q, Brolo A, Lum JJ, Andrews JL, Jirasek A. Raman spectroscopy and group and basis-restricted non negative matrix factorisation identifies radiation induced metabolic changes in human cancer cells. Sci Rep 2021; 11:3853. [PMID: 33594122 PMCID: PMC7886912 DOI: 10.1038/s41598-021-83343-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/11/2021] [Indexed: 12/12/2022] Open
Abstract
This work combines single cell Raman spectroscopy (RS) with group and basis restricted non-negative matrix factorisation (GBR-NMF) to identify individual biochemical changes associated with radiation exposure in three human cancer cell lines. The cell lines analysed were derived from lung (H460), breast (MCF7) and prostate (LNCaP) tissue and are known to display varying degrees of radio sensitivity due to the inherent properties of each cell type. The GBR-NMF approach involves the deconstruction of Raman spectra into component biochemical bases using a library of Raman spectra of known biochemicals present in the cells. Subsequently, scores are obtained on each of these bases which can be directly correlated with the contribution of each chemical to the overall Raman spectrum. We validated GBR-NMF through the correlation of GBR-NMF-derived glycogen scores with scores that were previously observed using principal component analysis (PCA). Phosphatidylcholine, glucose, arginine and asparagine showed a distinct differential score pattern between radio-resistant and radio-sensitive cell types. In summary, the GBR-NMF approach allows for the monitoring of individual biochemical radiation-response dynamics previously unattainable with more traditional PCA-based approaches.
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Affiliation(s)
- Kirsty Milligan
- Department of Physics, The University of British Columbia, Kelowna, Canada
| | - Xinchen Deng
- Department of Physics, The University of British Columbia, Kelowna, Canada
| | - Phillip Shreeves
- Department of Statistics, The University of British Columbia, Kelowna, Canada
| | - Ramie Ali-Adeeb
- Department of Physics, The University of British Columbia, Kelowna, Canada
| | | | - Alexandre Brolo
- Department of Chemistry, University of Victoria, Victoria, Canada
| | - Julian J Lum
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, Canada
| | - Jeffrey L Andrews
- Department of Statistics, The University of British Columbia, Kelowna, Canada
| | - Andrew Jirasek
- Department of Physics, The University of British Columbia, Kelowna, Canada.
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Albayrak G, Demirtas Korkmaz F. Memantine shifts cancer cell metabolism via AMPK1/2 mediated energetic switch in A549 lung cancer cells. EXCLI JOURNAL 2021; 20:223-231. [PMID: 34121969 PMCID: PMC8192876 DOI: 10.17179/excli2020-2890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/02/2021] [Indexed: 11/10/2022]
Abstract
Memantine is used to prevent glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. As glutamine is one of the major source of anabolism in fast growing cancer cells, we aimed to interfere with the cancer cell metabolism in A549 lung cancer cells by using memantine. The effects of memantine on cell cycle progression and cell death in A549 cells were assessed by MTT assay and PI staining. Cells were treated with 0.25 mM memantine for 48 hours and then cell metabolism (AMPKA1, AMPKA2, HIF1A, B-catenin, PKM), apoptosis (p53, p21, Bax, Bcl-XL, NOXA, PUMA) and autophagy related (LC3B-I, LC3B-II, SQSTM1) mRNA and protein expressions were investigated by RT-qPCR and western blotting. Memantine decreased cell viability significantly in a concentration-dependent manner by inducing G0/G1 cell cycle arrest. Our results suggest that memantine activates AMPK1/2 significantly (p=0.039 and p=0.0105) that led cells through apoptosis and autophagy by decreasing cancer cell metabolism regulators like HIF1A, B-catenin and PKM as the consequence of this energetic shift. Memantine represents a useful tool to target metabolism in cancer cells. Therefore, it might be used a new repurposed drug in cancer treatment.
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Affiliation(s)
- Gulsah Albayrak
- Department of Medical Biology, Faculty of Medicine, Ufuk University, Ankara, Turkey
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Mabate B, Daub CD, Malgas S, Edkins AL, Pletschke BI. Fucoidan Structure and Its Impact on Glucose Metabolism: Implications for Diabetes and Cancer Therapy. Mar Drugs 2021; 19:md19010030. [PMID: 33440853 PMCID: PMC7826564 DOI: 10.3390/md19010030] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 12/31/2020] [Accepted: 01/07/2021] [Indexed: 12/16/2022] Open
Abstract
Fucoidans are complex polysaccharides derived from brown seaweeds which consist of considerable proportions of L-fucose and other monosaccharides, and sulphated ester residues. The search for novel and natural bioproduct drugs (due to toxicity issues associated with chemotherapeutics) has led to the extensive study of fucoidan due to reports of it having several bioactive characteristics. Among other fucoidan bioactivities, antidiabetic and anticancer properties have received the most research attention in the past decade. However, the elucidation of the fucoidan structure and its biological activity is still vague. In addition, research has suggested that there is a link between diabetes and cancer; however, limited data exist where dual chemotherapeutic efforts are elucidated. This review provides an overview of glucose metabolism, which is the central process involved in the progression of both diseases. We also highlight potential therapeutic targets and show the relevance of fucoidan and its derivatives as a candidate for both cancer and diabetes therapy.
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Affiliation(s)
- Blessing Mabate
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
| | - Chantal Désirée Daub
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
| | - Samkelo Malgas
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
| | - Adrienne Lesley Edkins
- Biomedical Biotechnology Research Unit, Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa;
| | - Brett Ivan Pletschke
- Enzyme Science Programme (ESP), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa; (B.M.); (C.D.D.); (S.M.)
- Correspondence: ; Tel.: +27-46-603-8081; Fax: +27-46-603-7576
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Liu Z, Sun T, Zhang Z, Bi J, Kong C. An 18-gene signature based on glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer. Genomics 2021; 113:896-907. [PMID: 33096258 DOI: 10.1016/j.ygeno.2020.10.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/23/2020] [Accepted: 10/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Glucose metabolism and DNA methylation play important roles in cancers. We aimed to identify glucose metabolism-related genes that were DNA methylation associated to establish a prognostic signature of bladder cancer (BLCA). METHODS With BLCA sample transcriptome data from The Cancer Genome Atlas (TCGA) and methylation data from TCGA 450 K microarray, glucose metabolism-related genes associated to prognosis and DNA methylation were identified and a prognostic signature was established. GSEA and WGCNA analysis were performed and two genes, UCHL1 and PYCR1, were selected for functional validations. RESULTS 18 target genes were identified and the signature based on them was considered an effective and independent prognostic factor. Several pathways were enriched in the high-risk group by GSEA and three modules of genes were identified by WGCNA. UCHL1 and PYCR1 proliferated proliferation, migration and invasion ability of bladder cancer cells. CONCLUSIONS The 18-gene signature is an independent prognostic factor for bladder cancer patients.
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Affiliation(s)
- Zhuonan Liu
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China
| | - Tianshui Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Zhe Zhang
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China
| | - Jianbin Bi
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China.
| | - Chuize Kong
- Department of Urology, Fist Hospital of China Medical University, School of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang City, Liaoning Province 110004, PR China.
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A Novel Seventeen-Gene Metabolic Signature for Predicting Prognosis in Colon Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4845360. [PMID: 33282950 PMCID: PMC7685801 DOI: 10.1155/2020/4845360] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/28/2020] [Accepted: 10/18/2020] [Indexed: 02/08/2023]
Abstract
A metabolic disorder is considered one of the hallmarks of cancer. Multiple differentially expressed metabolic genes have been identified in colon cancer (CC), and their biological functions and prognostic values have been well explored. The purpose of the present study was to establish a metabolic signature to optimize the prognostic prediction in CC. The related data were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) database, and Gene Expression Omnibus (GEO) combined with GSE39582 set, GSE17538 set, GSE33113 set, and GSE37892 set. The differentially expressed metabolic genes were selected for univariate Cox regression and lasso Cox regression analysis using TCGA and GTEx datasets. Finally, a seventeen-gene metabolic signature was developed to divide patients into a high-risk group and a low-risk group. Patients in the high-risk group presented poorer prognosis compared to the low-risk group in both TCGA and GEO datasets. Moreover, gene set enrichment analyses demonstrated multiple significantly enriched metabolism-related pathways. To sum up, our study described a novel seventeen-gene metabolic signature for prognostic prediction of colon cancer.
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46
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Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity. Int J Mol Sci 2020; 21:ijms21218363. [PMID: 33171818 PMCID: PMC7664620 DOI: 10.3390/ijms21218363] [Citation(s) in RCA: 216] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 01/18/2023] Open
Abstract
Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid’s role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.
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47
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Regulation of Glycolysis by Non-coding RNAs in Cancer: Switching on the Warburg Effect. MOLECULAR THERAPY-ONCOLYTICS 2020; 19:218-239. [PMID: 33251334 PMCID: PMC7666327 DOI: 10.1016/j.omto.2020.10.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The “Warburg effect” describes the reprogramming of glucose metabolism away from oxidative phosphorylation toward aerobic glycolysis, and it is one of the hallmarks of cancer cells. Several factors can be involved in this process, but in this review, the roles of non-coding RNAs (ncRNAs) are highlighted in several types of human cancer. ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, can all affect metabolic enzymes and transcription factors to promote glycolysis and modulate glucose metabolism to enhance the progression of tumors. In particular, the 5′-AMP-activated protein kinase (AMPK) and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways are associated with alterations in ncRNAs. A better understanding of the roles of ncRNAs in the Warburg effect could ultimately lead to new therapeutic approaches for suppressing cancer.
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48
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Rochani AK, Wheatley M, Oeffinger BE, Eisenbrey JR, Kaushal G. LC-MS based stability-indicating method for studying the degradation of lonidamine under physical and chemical stress conditions. Res Pharm Sci 2020; 15:312-322. [PMID: 33312209 PMCID: PMC7714013 DOI: 10.4103/1735-5362.293509] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/15/2020] [Accepted: 04/27/2020] [Indexed: 12/27/2022] Open
Abstract
Background and purpose: Lonidamine is a hexokinase II inhibitor, works as an anticancer molecule, and is extensively explored in clinical trials. Limited information prevails about the stability-indicating methods which could determine the forced degradation of lonidamine under stressed conditions. Hence, we report the use of a rapid, sensitive, reproducible, and highly accurate liquid chromatography and mass spectrometry method to analyze lonidamine degradation. Experimental approach: The Xbridge BEH shield reverse phase C18 column (2.5 μm, 4.6 × 75 mm) using isocratic 50:50 water: acetonitrile with 0.1% formic acid can detect lonidamine with help of mass spectrometer in tandem with an ultraviolet (UV) detector at 260 nm wavelength. Findings/ Results: A linear curve with r2 > 0.99 was obtained for tandem liquid chromatography-mass spectrometry (LC-MS)-UV based detections. This study demonstrated (in the present set up of isocratic elution) that LC-MS based detection has a relatively high sensitivity (S/N (10 ng/mL): 220 and S/N (20 ng/mL): 945) and accuracy at lower detection and quantitation levels, respectively. In addition to developing the LC-MS method, we also report that the current method is stability-indicating and shows that lonidamine gets degraded over time under all three stress conditions; acidic, basic, and oxidative. Conclusion and implications: LC-MS based quantitation of lonidamine proved to be a better method compared to high-performance liquid chromatography (HPLC)-UV detections for mapping lonidamine degradation. This is the first report on the stability-indicating method for studying the forced degradation of lonidamine using LC-MS method.
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Affiliation(s)
- Ankit Kanaiyalal Rochani
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, USA
| | - Margaret Wheatley
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, USA
| | - Brian Edward Oeffinger
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, USA
| | | | - Gagan Kaushal
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, USA
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49
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Benny S, Mishra R, Manojkumar MK, Aneesh TP. From Warburg effect to Reverse Warburg effect; the new horizons of anti-cancer therapy. Med Hypotheses 2020; 144:110216. [PMID: 33254523 DOI: 10.1016/j.mehy.2020.110216] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/11/2020] [Accepted: 08/20/2020] [Indexed: 12/11/2022]
Abstract
An old ideology of killing the cancer cells by starving them is the underlying concept of the Warburg effect. It is the process of aerobic glycolysis exhibited by the cancer cells irrespective of anaerobic glycolysis or mitochondrial oxidative phosphorylation following by their healthy counterparts. Dr Otto Heinrich Warburg proposed this abnormal metabolic behaviour of tumour cells in 1920. This phenomenon illustrates the metabolic switching in tumour cells from oxidative phosphorylation to aerobic glycolysis triggered by an injury to the mitochondrial respiration. A modernised perspective of the Warburg hypothesis termed the Reverse Warburg effect introduced in 2009, with a two-compartment model describing the metabolic symbiosis between cancer cells and its neighbouring stromal cells or cancer-associated fibroblasts. This theory is elucidating the aerobic glycolysis occurring in cancer-associated fibroblasts which leads to the generation and deposition of the lactate in tumour microenvironment along with its significance. The transportation of lactate to and from the cancer cell and extracellular space is facilitated by the lactate transporters called monocarboxylate transporters. This lactate generated irrespective of the hypoxic or aerobic conditions acts as a primary metabolic fuel for the cancer cells. Besides, it will create a tumour microenvironment that is favouring the progression and metastasis of malignancy through several means. Overall, the lactate produced through this metabolic reprogramming is supporting and worsening the conditions of cancer. The concept of the Reverse Warburg effect proposes a new anti-cancer treatment modality by preventing the generation and transport of lactate through the inhibition of monocarboxylate transporters and in turn, defeating the cancer disease by arresting the cancer cells along with silencing tumour microenvironment.
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Affiliation(s)
- Sonu Benny
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala 682041, India
| | - Rohan Mishra
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala 682041, India
| | - Maneesha K Manojkumar
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala 682041, India
| | - T P Aneesh
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala 682041, India.
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Purushottam Dharaskar S, Paithankar K, Kanugovi Vijayavittal A, Shabbir Kara H, Amere Subbarao S. Mitochondrial chaperone, TRAP1 modulates mitochondrial dynamics and promotes tumor metastasis. Mitochondrion 2020; 54:92-101. [PMID: 32784002 DOI: 10.1016/j.mito.2020.08.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/26/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022]
Abstract
Mitochondria play a central role in regulating cellular energy metabolism. However, the present understanding of mitochondria has changed from its unipotent functions to pluripotent and insists on understanding the role of mitochondria not only in regulating the life and death of cells, but in pathological conditions such as cancer. Unlike other cellular organelles, subtle alterations in mitochondrial organization may significantly influence the balance between metabolic networks and cellular behavior. Therefore, the delicate balance between the fusion and fission dynamics of mitochondrion can indicate cell fate. Here, we present mitochondrial chaperone TRAP1 influence on mitochondrial architecture and its correlation with tumor growth and metastasis. We show that TRAP1 overexpression (TRAP1 OE) promotes mitochondrial fission, whereas, TRAP1 knockdown (TRAP1 KD) promotes mitochondrial fusion. Interestingly, TRAP1 OE or KD had a negligible effect on mitochondrial integrity. However, TRAP1 OE cells exhibited enhanced proliferative potential, while TRAP1 KD cells showing increased doubling time. Further, TRAP1 dependent mitochondrial dynamic alterations appeared to be unique since mitochondrial localization of TRAP1 is a mandate for dynamic changes. The expression patterns of fusion and fission genes have failed to correlate with TRAP1 expression, indicating a possibility that the dynamic changes can be independent of these genes. In agreement with enhanced proliferative potential, TRAP1 OE cells also exhibited enhanced migration in vitro and tumor metastasis in vivo. Further, TRAP1 OE cells showed altered homing properties, which may challenge site-specific anticancer treatments. Our findings unravel the TRAP1 role in tumor metastasis, which is in addition to altered energy metabolism.
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Affiliation(s)
- Shrikant Purushottam Dharaskar
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, Telangana, India; AcSIR - Academy of Scientific & Innovative Research, Government of India, India
| | - Khanderao Paithankar
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, Telangana, India
| | | | - Hatim Shabbir Kara
- Presently at Life Sciences & Chemistry, Jacobs University Bremen gGmbh, Bremen, Germany
| | - Sreedhar Amere Subbarao
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, Telangana, India.
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