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Jiang K, Liu H, Chen X, Wang Z, Wang X, Gu X, Tong Y, Ba X, He Y, Wu J, Deng W, Wang Q, Tang K. Reprogramming of Glucose Metabolism by Nanocarriers to Improve Cancer Immunotherapy: Recent Advances and Applications. Int J Nanomedicine 2025; 20:4201-4234. [PMID: 40207307 PMCID: PMC11980946 DOI: 10.2147/ijn.s513207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/20/2025] [Indexed: 04/11/2025] Open
Abstract
Although immunotherapy has made significant progress in cancer treatment, its limited responsiveness has greatly hindered widespread clinical application. The Warburg effect in tumor cells creates a tumor microenvironment (TME) characterized by hypoxia, low glucose levels, and high lactate levels, which severely inhibits the antitumor immune response. Consequently, targeting glucose metabolism to reprogram the TME is considered an effective strategy for reversing immunosuppression and immune evasion. Numerous studies have been conducted on enhancing cancer immunotherapy efficacy through the delivery of glucose metabolism modulators via nanocarriers. This review provides a comprehensive overview of the glucose metabolic characteristics of tumors and their impacts on the immune system, as well as nanodelivery strategies targeting glucose metabolism to enhance immunotherapy. These strategies include inhibiting key glycolytic enzymes, blocking glucose and lactate transporters, and utilizing glucose oxidase and lactate oxidase. Furthermore, this article reviews recent advancements in synergistic antitumor therapy involving glucose metabolism-targeted therapy combined with other treatments, such as chemotherapy, radiotherapy (RT), phototherapy, and immunotherapy. Finally, we discuss the limitations and future prospects of nanotechnology targeting glucose metabolism therapy, hoping to provide new directions and ideas to improve cancer immunotherapy.
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Affiliation(s)
- Kehua Jiang
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China
| | - Hongming Liu
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China
| | - Xiaolong Chen
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China
| | - Zhen Wang
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China
| | - Xiaodong Wang
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China
| | - Xiaoya Gu
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, People’s Republic of China
| | - Yonghua Tong
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Xiaozhuo Ba
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Yu He
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Jian Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Wen Deng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Qing Wang
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China
| | - Kun Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
- Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, People’s Republic of China
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Cheng B, Liu J, Gao L, Zhu Z, Yang Y, Liu S, Wu X. EMB-driven glioblastoma multiforme progression via the MCT4/GPX3 axis: therapeutic inhibition by Ganxintriol A. J Transl Med 2025; 23:272. [PMID: 40038742 PMCID: PMC11881305 DOI: 10.1186/s12967-025-06290-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 02/23/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Embigin (EMB) is a transmembrane glycoprotein highly expressed in glioblastoma multiforme (GBM), yet its role in GBM progression remains unclear. In this study, we investigate the function of intracellular EMB in promoting GBM progression and evaluate the effect of Ganxintriol A, a traditional Chinese herbal extract, in GBM treatment. METHODS Bioinformatics datasets were utilized to assess EMB expression and its prognostic value in GBM patients. In vitro experiments such as PCR、western blot,CCK8,transwell,wound healing,clone formation and flow cytometry assays were conducted to examine EMB's biological functions and underlying mechanisms in GBM cell lines. Additionally, we constructed a subcutaneous tumor model in nude mice and evaluated the effect of traditional Chinese medicine extract Ganxintriol A on the progression of GBM through in vivo and in vitro experiments. RESULTS EMB is highly expressed in GBM and is associated with poor prognosis in GBM patients. EMB overexpression accelerated GBM progression, whereas EMB knockdown had the opposite effect. Further analysis revealed that EMB upregulated epithelial-mesenchymal transition (EMT) and glycolysis while maintaining glutathione (GSH) redox balance by inducing monocarboxylate transporter 4 (MCT4) and glutathione peroxidase 3 (GPX3) expression. Treatment with Ganxintriol A significantly downregulated EMB expression, effectively inhibiting GBM progression both in vitro and in vivo. CONCLUSIONS This study highlights EMB as an independent prognostic biomarker for GBM and reveals a novel mechanism by which EMB drives GBM progression. Additionally, Ganxintriol A is identified as a promising therapeutic candidate for GBM treatment.
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Affiliation(s)
- Bo Cheng
- Department of Psychiatry, The Affiliated Xuzhou Eastern Hospital of Xuzhou Medical University, 379 Tongshan Road, Xuzhou, 221000, China
- Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, Shanghai, 200292, China
| | - Jing Liu
- Department of Neurology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou No. 1 People's Hospital, 269 University Road, Xuzhou, 221000, China
| | - Ling Gao
- Department of Pharmacy, The Affiliated Huaihai Hospital of Xuzhou Medical University, The 71st Group Army Hospital of CPLA Army, 226 Tongshan Road, Xuzhou, 221000, China
| | - Ziwen Zhu
- Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, Shanghai, 200292, China
| | - Yang Yang
- Department of Pharmacy, The Affiliated Huaihai Hospital of Xuzhou Medical University, The 71st Group Army Hospital of CPLA Army, 226 Tongshan Road, Xuzhou, 221000, China
| | - Shangqi Liu
- Department of Neurology, Xuzhou Central Hospital, the Affiliated Xuzhou Clinical College of Xuzhou Medical University, 199 Jiefang South Road, Xuzhou, 221000, China
| | - Xiaojin Wu
- Department of Radiation Oncology, Xuzhou Central Hospital, the Affiliated Xuzhou Clinical College of Xuzhou Medical University, 199 Jiefang South Road, Xuzhou, 221000, China.
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Ye Y, Cao Z. Glucose Metabolism and Glucose Transporters in Head and Neck Squamous Cell Carcinoma. Cancer Invest 2024; 42:827-844. [PMID: 39324504 DOI: 10.1080/07357907.2024.2407424] [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: 05/11/2024] [Accepted: 09/18/2024] [Indexed: 09/27/2024]
Abstract
Head and neck squamous cell carcinoma ranks seventh globally in malignancy prevalence, with persistent high mortality rates despite treatment advancements. Glucose, pivotal in cancer metabolism via the Warburg effect, enters cells via glucose transporters, notably GLUT proteins. Glycolysis, aerobic oxidation, and the pentose phosphate pathway in glucose metabolism significantly impact HNSCC progression. HNSCC exhibits elevated expression of glucose metabolism enzymes and GLUT proteins, correlating with prognosis. Heterogeneity in HNSCC yields varied metabolic profiles, influenced by factors like HPV status and disease stage. This review highlights glucose metabolism's role and potential as therapeutic targets and cancer imaging tracers in HNSCC.
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Affiliation(s)
- Yanyan Ye
- Department of Otolaryngology, Shulan (Hangzhou) Hospital, affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Zaizai Cao
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Hsu FT, Chen YT, Chin YC, Chang LC, Chiang SC, Yang LX, Liu HS, Yueh PF, Tu HL, He RY, Jeng LB, Shyu WC, Hu SH, Chiang IT, Liu YC, Chiu YC, Wu GC, Yu CC, Su WP, Huang CC. Harnessing the Power of Sugar-Based Nanoparticles: A Drug-Free Approach to Enhance Immune Checkpoint Inhibition against Glioblastoma and Pancreatic Cancer. ACS NANO 2024; 18:28764-28781. [PMID: 39383310 DOI: 10.1021/acsnano.4c07903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/11/2024]
Abstract
Cancer cells have a high demand for sugars and express diverse carbohydrate receptors, offering opportunities to improve delivery with multivalent glycopolymer materials. However, effectively delivering glycopolymers to tumors while inhibiting cancer cell activity, altering cellular metabolism, and reversing tumor-associated macrophage (TAM) polarization to overcome immunosuppression remains a challenging area of research due to the lack of reagents capable of simultaneously achieving these objectives. Here, the glycopolymer-like condensed nanoparticle (∼60 nm) was developed by a one-pot carbonization reaction with a single precursor, promoting multivalent interactions for the galactose-related receptors of the M2 macrophage (TAM) and thereby regulating the STAT3/NF-κB pathways. The subsequently induced M2-to-M1 transition was increased with the condensed level of glycopolymer-like nanoparticles. We found that the activation of the glycopolymer-like condensed galactose (CG) nanoparticles influenced monocarboxylate transporter 4 (MCT-4) function, which caused inhibited lactate efflux (similar to inhibitor effects) from cancer cells. Upon internalization via galactose-related endocytosis, CG NPs induced cellular reactive oxygen species (ROS), leading to dual functionalities of cancer cell death and M2-to-M1 macrophage polarization, thereby reducing the tumor's acidic microenvironment and immunosuppression. Blocking the nanoparticle-MCT-4 interaction with antibodies reduced their toxicity in glioblastoma (GBM) and affected macrophage polarization. In orthotopic GBM and pancreatic cancer models, the nanoparticles remodeled the tumor microenvironment from "cold" to "hot", enhancing the efficacy of anti-PD-L1/anti-PD-1 therapy by promoting macrophage polarization and activating cytotoxic T lymphocytes (CTLs) and dendritic cells (DCs). These findings suggest that glycopolymer-like nanoparticles hold promise as a galactose-elicited adjuvant for precise immunotherapy, particularly in targeting hard-to-treat cancers.
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Affiliation(s)
- Fei-Ting Hsu
- Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan, R.O.C
| | - Ying-Tzu Chen
- Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan, R.O.C
- Department of Dentistry, National Yang Ming Chiao Tung University, Taipei 112, Taiwan, R.O.C
| | - Yu-Cheng Chin
- Department of Photonics, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
| | - Li-Chan Chang
- Institute of Clinical Medicine College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
| | - Shu-Chin Chiang
- Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan, R.O.C
| | - Li-Xing Yang
- Department of Photonics, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
| | - Hua-Shan Liu
- School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan, R.O.C
- International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan, R.O.C
| | - Po-Fu Yueh
- Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan, R.O.C
| | - Hsiung-Lin Tu
- Institute of Chemistry, Academia Sinica, Nangang, Taipei 115, Taiwan, R.O.C
| | - Ruei-Yu He
- Institute of Chemistry, Academia Sinica, Nangang, Taipei 115, Taiwan, R.O.C
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan, R.O.C
- Cell Therapy Center, China Medical University Hospital, Taichung 404, Taiwan, R.O.C
- School of Medicine, China Medical University, Taichung 404, Taiwan, R.O.C
| | - Woei-Cheang Shyu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan, R.O.C
- Department of Occupational Therapy, Asia University, Taichung 413, Taiwan, R.O.C
- Translational Medicine Research Center and Department of Neurology, China Medical University Hospital, Taichung 404, Taiwan, R.O.C
| | - Shang-Hsiu Hu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, R.O.C
| | - I-Tsang Chiang
- Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, Taiwan, R.O.C
- Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Lukang, Changhua 505, Taiwan, R.O.C
- Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 406, Taiwan, R.O.C
- Medical Administrative Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan, R.O.C
| | - Yu-Chang Liu
- Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, Taiwan, R.O.C
- Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Lukang, Changhua 505, Taiwan, R.O.C
- Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 406, Taiwan, R.O.C
| | - Yi-Chun Chiu
- Division of Urology, Department of Surgery, Yangming Branch, Taipei City Hospital, Taipei 111, Taiwan, R.O.C
- Department of Urology, College of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan, R.O.C
- Department of Exercise and Health Sciences, University of Taipei, Taipei 111, Taiwan, R.O.C
| | - Guan-Chun Wu
- Institute of Chemistry, Academia Sinica, Nangang, Taipei 115, Taiwan, R.O.C
- Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, R.O.C
| | - Ching-Ching Yu
- Institute of Chemistry, Academia Sinica, Nangang, Taipei 115, Taiwan, R.O.C
- Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, R.O.C
| | - Wen-Pin Su
- Institute of Clinical Medicine College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
- Departments of Oncology and Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan, R.O.C
- Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan, R.O.C
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
| | - Chih-Chia Huang
- Department of Photonics, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C
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Nicolini A, Ferrari P. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front Immunol 2024; 15:1353787. [PMID: 39119332 PMCID: PMC11306065 DOI: 10.3389/fimmu.2024.1353787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/04/2024] [Indexed: 08/10/2024] Open
Abstract
Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology, Department of Medical and Oncological Area, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy
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Chatterjee P, Karn R, Emerson. I A, Banerjee S. Deciphering the Chemotherapeutic Role of the Aryl Hydrocarbon Receptor Antagonist Resveratrol against the High-Penetrance Genes of Triple-Negative Breast Cancer. ACS OMEGA 2024; 9:30350-30363. [PMID: 39035954 PMCID: PMC11256332 DOI: 10.1021/acsomega.4c01317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 06/04/2024] [Accepted: 06/07/2024] [Indexed: 07/23/2024]
Abstract
In addition to several other malignancies, the ligand-activated aryl hydrocarbon receptor (AhR) signaling pathway has been found to enhance the risk of triple-negative breast cancer (TNBC). Many natural compounds of pharmaceutical importance are identified as antagonistic exogenous ligands of AhR. The expressional lack of hormone receptors coupled with adverse prognosis leads to the absence of molecular-targeted therapy in TNBC. Hence, discovering low-cost therapeutic alternatives involving the identification of effective biomarkers is an urgent necessity. This study investigates the binding mechanism of resveratrol, a dietary exogenous AhR ligand against the high-penetrance genes in TNBC, viz., PALB2, TP53, PTEN, STK11, BRCA1, and BRCA2. Post-pharmacokinetic evaluation, molecular docking revealed the binding energy scores of resveratrol against the six TNBC high-penetrance receptors. The results obtained from docking were confirmed by molecular dynamics simulation including principal component analysis, calculation of total interaction energy, and free-energy landscape computation. PALB2 emerged as a promising therapeutic receptor of resveratrol. Furthermore, the PALB2-resveratrol binding dynamics were evaluated against olaparib, an FDA-approved standardized TNBC inhibitor. Our study reveals comparatively better chemistry of PALB2-resveratrol than PALB2-olaparib. Considering the current surge in the discovery of precision medicine in biomarker-based cancer therapeutics, this study proposes PALB2-resveratrol as a unique drug-receptor combination thus awaiting validation through in vitro studies.
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Affiliation(s)
| | | | - Arnold Emerson. I
- School of BioSciences and
Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
| | - Satarupa Banerjee
- School of BioSciences and
Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
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Smeets EMM, Trajkovic-Arsic M, Geijs D, Karakaya S, van Zanten M, Brosens LAA, Feuerecker B, Gotthardt M, Siveke JT, Braren R, Ciompi F, Aarntzen EHJG. Histology-Based Radiomics for [ 18F]FDG PET Identifies Tissue Heterogeneity in Pancreatic Cancer. J Nucl Med 2024; 65:1151-1159. [PMID: 38782455 DOI: 10.2967/jnumed.123.266262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Radiomics features can reveal hidden patterns in a tumor but usually lack an underlying biologic rationale. In this work, we aimed to investigate whether there is a correlation between radiomics features extracted from [18F]FDG PET images and histologic expression patterns of a glycolytic marker, monocarboxylate transporter-4 (MCT4), in pancreatic cancer. Methods: A cohort of pancreatic ductal adenocarcinoma patients (n = 29) for whom both tumor cross sections and [18F]FDG PET/CT scans were available was used to develop an [18F]FDG PET radiomics signature. By using immunohistochemistry for MCT4, we computed density maps of MCT4 expression and extracted pathomics features. Cluster analysis identified 2 subgroups with distinct MCT4 expression patterns. From corresponding [18F]FDG PET scans, radiomics features that associate with the predefined MCT4 subgroups were identified. Results: Complex heat map visualization showed that the MCT4-high/heterogeneous subgroup was correlating with a higher MCT4 expression level and local variation. This pattern linked to a specific [18F]FDG PET signature, characterized by a higher SUVmean and SUVmax and second-order radiomics features, correlating with local variation. This MCT4-based [18F]FDG PET signature of 7 radiomics features demonstrated prognostic value in an independent cohort of pancreatic cancer patients (n = 71) and identified patients with worse survival. Conclusion: Our cross-modal pipeline allows the development of PET scan signatures based on immunohistochemical analysis of markers of a particular biologic feature, here demonstrated on pancreatic cancer using intratumoral MCT4 expression levels to select [18F]FDG PET radiomics features. This study demonstrated the potential of radiomics scores to noninvasively capture intratumoral marker heterogeneity and identify a subset of pancreatic ductal adenocarcinoma patients with a poor prognosis.
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Affiliation(s)
- Esther M M Smeets
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marija Trajkovic-Arsic
- German Cancer Consortium, partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy and Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Daan Geijs
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sinan Karakaya
- German Cancer Consortium, partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy and Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Monica van Zanten
- Department of Pathology, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Benedikt Feuerecker
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Radiology, School of Medicine, Technical University of Munich, Munich, Germany
- German Cancer Consortium, partner site Munich, a partnership between DKFZ and Technical University of Munich, Munich, Germany
- Department of Radiology, Ludwig Maximilians University, Munich, Germany; and
| | - Martin Gotthardt
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jens T Siveke
- German Cancer Consortium, partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy and Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- National Center for Tumor Diseases West, Campus Essen, Essen, Germany
| | - Rickmer Braren
- Department of Radiology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Francesco Ciompi
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Erik H J G Aarntzen
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands;
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8
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Cho H, Huh KM, Cho HJ, Kim B, Shim MS, Cho YY, Lee JY, Lee HS, Kwon YJ, Kang HC. Beyond nanoparticle-based oral drug delivery: transporter-mediated absorption and disease targeting. Biomater Sci 2024; 12:3045-3067. [PMID: 38712883 DOI: 10.1039/d4bm00313f] [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: 05/08/2024]
Abstract
Various strategies at the microscale/nanoscale have been developed to improve oral absorption of therapeutics. Among them, gastrointestinal (GI)-transporter/receptor-mediated nanosized drug delivery systems (NDDSs) have drawn attention due to their many benefits, such as improved water solubility, improved chemical/physical stability, improved oral absorption, and improved targetability of their payloads. Their therapeutic potential in disease animal models (e.g., solid tumors, virus-infected lungs, metastasis, diabetes, and so on) has been investigated, and could be expanded to disease targeting after systemic/lymphatic circulation, although the detailed paths and mechanisms of endocytosis, endosomal escape, intracellular trafficking, and exocytosis through the epithelial cell lining in the GI tract are still unclear. Thus, this review summarizes and discusses potential GI transporters/receptors, their absorption and distribution, in vivo studies, and potential sequential targeting (e.g., oral absorption and disease targeting in organs/tissues).
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Affiliation(s)
- Hana Cho
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
| | - Kang Moo Huh
- Department of Polymer Science and Engineering & Materials Science and Engineering, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Hyun Ji Cho
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
| | - Bogeon Kim
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
| | - Min Suk Shim
- Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Yong-Yeon Cho
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
- Regulated Cell Death (RCD) Control Material Research Institute, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Joo Young Lee
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
- Regulated Cell Death (RCD) Control Material Research Institute, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Hye Suk Lee
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
- Regulated Cell Death (RCD) Control Material Research Institute, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Young Jik Kwon
- Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA
| | - Han Chang Kang
- Department of Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
- Regulated Cell Death (RCD) Control Material Research Institute, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
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Pandey S, Singh R, Habib N, Tripathi RM, Kushwaha R, Mahdi AA. Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia. Asian Pac J Cancer Prev 2024; 25:1121-1134. [PMID: 38679971 PMCID: PMC11162727 DOI: 10.31557/apjcp.2024.25.4.1121] [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: 08/18/2023] [Accepted: 04/20/2024] [Indexed: 05/01/2024] Open
Abstract
Metabolic reprogramming occurs to meet cancer cells' high energy demand. Its function is essential to the survival of malignancies. Comparing cancer cells to non-malignant cells has revealed that cancer cells have altered metabolism. Several pathways, particularly mTOR, Akt, PI3K, and HIF-1 (hypoxia-inducible factor-1) modulate the metabolism of cancer. Among other aspects of cancer biology, gene expression in metabolism, survival, invasion, proliferation, and angiogenesis of cells are controlled by HIF-1, a vital controller of cellular responsiveness to hypoxia. This article examines various cancer cell metabolisms, metabolic alterations that can take place in cancer cells, metabolic pathways, and molecular aspects of metabolic alteration in cancer cells placing special attention on the consequences of hypoxia-inducible factor and summarising some of their novel targets in the treatment of cancer including leukemia. A brief description of HIF-1α's role and target in a few common types of hematological malignancies (leukemia) is also elucidated in the present article.
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Affiliation(s)
- Sandeep Pandey
- Department of Biochemistry, King George’s Medical University, Lucknow, U.P., India.
| | - Ranjana Singh
- Department of Biochemistry, King George’s Medical University, Lucknow, U.P., India.
| | - Nimra Habib
- Department of Biochemistry, King George’s Medical University, Lucknow, U.P., India.
| | - Ramesh Mani Tripathi
- Department of Biochemistry, King George’s Medical University, Lucknow, U.P., India.
| | - Rashmi Kushwaha
- Department of Pathology, King George’s Medical University, Lucknow, U.P., India.
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George’s Medical University, Lucknow, U.P., India.
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10
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Cheng Q, Shi X, Li Q, Wang L, Wang Z. Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305662. [PMID: 37941489 PMCID: PMC10797484 DOI: 10.1002/advs.202305662] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/15/2023] [Indexed: 11/10/2023]
Abstract
Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.
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Affiliation(s)
- Qian Cheng
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Xiao‐Lei Shi
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Qi‐Lin Li
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Lin Wang
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Zheng Wang
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Hubei Key Laboratory of Regenerative Medicine and Multi‐disciplinary Translational ResearchWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
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11
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Kim NI, Park MH, Kweon SS, Lee JS. Metabolic coupling in phyllodes tumor of the breast and its association with tumor progression. Oncol Lett 2023; 26:545. [PMID: 38020291 PMCID: PMC10660424 DOI: 10.3892/ol.2023.14132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 10/13/2023] [Indexed: 12/01/2023] Open
Abstract
There are markers of metabolic coupling in breast cancer. Loss of caveolin-1 (Cav-1) and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, serve an important role in metabolic coupling necessary for release and uptake of metabolites. However, the occurrence of these phenomena in phyllodes tumors (PTs) of the breast is unclear. A total of 101 PTs (60 benign, 26 borderline and 15 malignant) and nine breast tissue samples with no pathological lesions were analyzed. Immunohistochemical staining for Cav-1, MCT1 and MCT4 was performed using tissue microarray and their expression in both stromal and epithelial components was assessed. Cav-1 expression in PTs demonstrated a significant decrease in the stromal component compared with that in the normal breast tissues (P<0.001). MCT1 expression in both epithelial and stromal components was significantly increased in PTs, compared with that in normal breast tissues (both P<0.001). Stromal MCT1 and MCT4 expression were different depending on tumor grade of PTs, and stromal MCT1 expression significantly increased with increasing tumor grade (P<0.001). Although not statistically significant, stromal Cav-1 expression notably decreased with increases in PT grade. High stromal MCT1 expression was significantly associated with lower disease-free survival rate in comparison with low stromal MCT1 expression (P<0.05). These results suggested that changes in protein expression of Cav-1, MCT1 and MCT4 may be associated with tumorigenesis and progression of PTs of the breast.
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Affiliation(s)
- Nah Ihm Kim
- Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Min Ho Park
- Department of Surgery, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Ji Shin Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
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12
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Shuvalov O, Kirdeeva Y, Daks A, Fedorova O, Parfenyev S, Simon HU, Barlev NA. Phytochemicals Target Multiple Metabolic Pathways in Cancer. Antioxidants (Basel) 2023; 12:2012. [PMID: 38001865 PMCID: PMC10669507 DOI: 10.3390/antiox12112012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Cancer metabolic reprogramming is a complex process that provides malignant cells with selective advantages to grow and propagate in the hostile environment created by the immune surveillance of the human organism. This process underpins cancer proliferation, invasion, antioxidant defense, and resistance to anticancer immunity and therapeutics. Perhaps not surprisingly, metabolic rewiring is considered to be one of the "Hallmarks of cancer". Notably, this process often comprises various complementary and overlapping pathways. Today, it is well known that highly selective inhibition of only one of the pathways in a tumor cell often leads to a limited response and, subsequently, to the emergence of resistance. Therefore, to increase the overall effectiveness of antitumor drugs, it is advisable to use multitarget agents that can simultaneously suppress several key processes in the tumor cell. This review is focused on a group of plant-derived natural compounds that simultaneously target different pathways of cancer-associated metabolism, including aerobic glycolysis, respiration, glutaminolysis, one-carbon metabolism, de novo lipogenesis, and β-oxidation of fatty acids. We discuss only those compounds that display inhibitory activity against several metabolic pathways as well as a number of important signaling pathways in cancer. Information about their pharmacokinetics in animals and humans is also presented. Taken together, a number of known plant-derived compounds may target multiple metabolic and signaling pathways in various malignancies, something that bears great potential for the further improvement of antineoplastic therapy.
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Affiliation(s)
- Oleg Shuvalov
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Yulia Kirdeeva
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Alexandra Daks
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Olga Fedorova
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Sergey Parfenyev
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland;
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
| | - Nickolai A. Barlev
- Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia; (Y.K.); (A.D.); (O.F.)
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 20000, Kazakhstan
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13
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Oseguera M, Yau AA. Lactic acidosis in a patient with cancer. Clin Med (Lond) 2023; 23:615-617. [PMID: 38065594 PMCID: PMC11046607 DOI: 10.7861/clinmed.2023-0391] [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: 12/18/2023]
Abstract
Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially one undergoing chemotherapy, there is always concern for sepsis; however, in the otherwise clincially stable patient with cancer, type B lactic acidosis can also be related to their underlying malignancy. It is considered a haematological emergency given its high mortality rate. However, despite the urgency to treat type B lactic acidosis in these circumstances, treatment options beyond treatment of the malignancy are limited, and its presence portends a poor prognosis. This case highlights our current understanding of type B lactic acidosis and an approach to lactic acidosis evaluation in the cancer patient.
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Affiliation(s)
- Mayra Oseguera
- The Ohio State University Wexner Medical Center, Columbus, USA
| | - Amy A Yau
- The Ohio State University Wexner Medical Center, Columbus, USA
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14
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EL-Seedy A, Pellerin L, Page G, Ladeveze V. Identification of Intron Retention in the Slc16a3 Gene Transcript Encoding the Transporter MCT4 in the Brain of Aged and Alzheimer-Disease Model (APPswePS1dE9) Mice. Genes (Basel) 2023; 14:1949. [PMID: 37895298 PMCID: PMC10606527 DOI: 10.3390/genes14101949] [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: 09/21/2023] [Revised: 10/12/2023] [Accepted: 10/14/2023] [Indexed: 10/29/2023] Open
Abstract
The monocarboxylate transporter 4 (MCT4; Slc16a3) is expressed in the central nervous system, notably by astrocytes. It is implicated in lactate release and the regulation of glycolytic flux. Whether its expression varies during normal and/or pathological aging is unclear. As the presence of its mature transcript in the brain of young and old mice was determined, an unexpectedly longer RT-PCR fragment was detected in the mouse frontal cortex and hippocampus at 12 vs. 3 months of age. Cultured astrocytes expressed the expected 516 base pair (bp) fragment but treatment with IL-1β to mimic inflammation as can occur during aging led to the additional expression of a 928 bp fragment like that seen in aged mice. In contrast, cultured pericytes (a component of the blood-brain barrier) only exhibited the 516 bp fragment. Intriguingly, cultured endothelial cells constitutively expressed both fragments. When RT-PCR was performed on brain subregions of an Alzheimer mouse model (APPswePS1dE9), no fragment was detected at 3 months, while only the 928 bp fragment was present at 12 months. Sequencing of MCT4 RT-PCR products revealed the presence of a remaining intron between exon 2 and 3, giving rise to the longer fragment detected by RT-PCR. These results unravel the existence of intron retention for the MCT4 gene in the central nervous system. Such alternative splicing appears to increase with age in the brain and might be prominent in neurodegenerative diseases such as Alzheimer's disease. Hence, further studies in vitro and in vivo of intron 2 retention in the Slc16a3 gene transcript are required for adequate characterization concerning the biological roles of Slc16a3 isoforms in the context of aging and Alzheimer's disease pathology.
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Affiliation(s)
- Ayman EL-Seedy
- Laboratory of Cellular and Molecular Genetics, Department of Genetics, Alexandria University, Aflaton Street, El-Shatby, Alexandria 21545, Egypt;
- Neurovascular Unit and Cognitive Disorders (NEUVACOD), Faculty of Pharmacy (GP), Faculty of Fundamental and Applied Science (VL), University of Poitiers, Pôle Biologie Santé, 86073 Poitiers, France;
| | - Luc Pellerin
- IRMETIST, INSERM, Faculty of Medicine, University of Poitiers (U1313), CHU de Poitiers, 86021 Poitiers, France;
| | - Guylène Page
- Neurovascular Unit and Cognitive Disorders (NEUVACOD), Faculty of Pharmacy (GP), Faculty of Fundamental and Applied Science (VL), University of Poitiers, Pôle Biologie Santé, 86073 Poitiers, France;
| | - Veronique Ladeveze
- Neurovascular Unit and Cognitive Disorders (NEUVACOD), Faculty of Pharmacy (GP), Faculty of Fundamental and Applied Science (VL), University of Poitiers, Pôle Biologie Santé, 86073 Poitiers, France;
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15
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Zhang G, Cullen Q, Berishaj M, Deh K, Kim N, Keshari KR. [6,6'- 2 H 2 ] fructose as a deuterium metabolic imaging probe in liver cancer. NMR IN BIOMEDICINE 2023; 36:e4989. [PMID: 37336778 PMCID: PMC10585608 DOI: 10.1002/nbm.4989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 04/26/2023] [Accepted: 05/23/2023] [Indexed: 06/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. Imaging plays a crucial role in the early detection of HCC, although current methods are limited in their ability to characterize liver lesions. Most recently, deuterium metabolic imaging (DMI) has been demonstrated as a powerful technique for the imaging of metabolism in vivo. Here, we assess the metabolic flux of [6,6'-2 H2 ] fructose in cell cultures and in subcutaneous mouse models at 9.4 T. We compare these rates with the most widely used DMI probe, [6,6'-2 H2 ] glucose, exploring the possibility of developing 2 H fructose to overcome the limitations of glucose as a novel DMI probe for detecting liver tumors. Comparison of the in vitro metabolic rates implies their similar glycolytic metabolism in the TCA cycle due to comparable production rates of 2 H glutamate/glutamine (glx) for the two precursors, but overall higher glycolytic metabolism from 2 H glucose because of a higher production rate of 2 H lactate. In vivo kinetic studies suggest that HDO can serve as a robust reporter for the consumption of the precursors in liver tumors. As fructose is predominantly metabolized in the liver, deuterated water (HDO) produced from 2 H fructose is probably less contaminated from whole-body metabolism in comparison with glucose. Moreover, in studies of the normal liver, 2 H fructose is readily converted to 2 H glx, enabling the characterization of 2 H fructose kinetics. This overcomes a major limitation of previous 2 H glucose studies in the liver, which were unable to confidently discern metabolic flux due to overlapped signals of 2 H glucose and its metabolic product, 2 H glycogen. This suggests a unique role for 2 H fructose metabolism in HCC and the normal liver, making it a useful approach for assessing liver-related diseases and the progression to oncogenesis.
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Affiliation(s)
- Guannan Zhang
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | | | - Marjan Berishaj
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Kofi Deh
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Nathaniel Kim
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Kayvan R. Keshari
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Graduate School, New York, New York, USA
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16
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Liu T, Han S, Yao Y, Zhang G. Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment. Cancer Manag Res 2023; 15:957-975. [PMID: 37693221 PMCID: PMC10487743 DOI: 10.2147/cmar.s421771] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/30/2023] [Indexed: 09/12/2023] Open
Abstract
In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.
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Affiliation(s)
- Tian Liu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Shangcong Han
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China
| | - Yu Yao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Guiming Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
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17
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Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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18
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Taghehchian N, Samsami Y, Maharati A, Zangouei AS, Boroumand-Noughabi S, Moghbeli M. Molecular biology of microRNA-342 during tumor progression and invasion. Pathol Res Pract 2023; 248:154672. [PMID: 37413875 DOI: 10.1016/j.prp.2023.154672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/02/2023] [Indexed: 07/08/2023]
Abstract
Cancer is considered as one of the main causes of human deaths and health challenges in the world. Various factors are involved in the high death rate of cancer patients, including late diagnosis and drug resistance that result in treatment failure and tumor recurrence. Invasive diagnostic methods are one of the main reasons of late tumor detection in cancer patients. Therefore, it is necessary to investigate the molecular tumor biology to introduce efficient non-invasive markers. MicroRNAs (miRNAs) are involved in regulation of the cellular mechanisms such as cell proliferation, apoptosis, and migration. MiRNAs deregulations have been also frequently shown in different tumor types. Here, we discussed the molecular mechanisms of miR-342 during tumor growth. MiR-342 mainly functions as a tumor suppressor by the regulation of transcription factors and signaling pathways such as WNT, PI3K/AKT, NF-kB, and MAPK. Therefore, miR-342 mimics can be used as a reliable therapeutic strategy to inhibit the tumor cells growth. The present review can also pave the way to introduce the miR-342 as a non-invasive diagnostic/prognostic marker in cancer patients.
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Affiliation(s)
- Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yalda Samsami
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Boroumand-Noughabi
- Department of Hematology and Blood Bank, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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19
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Kumar V, Stewart JH. Immunometabolic reprogramming, another cancer hallmark. Front Immunol 2023; 14:1125874. [PMID: 37275901 PMCID: PMC10235624 DOI: 10.3389/fimmu.2023.1125874] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/02/2023] [Indexed: 06/07/2023] Open
Abstract
Molecular carcinogenesis is a multistep process that involves acquired abnormalities in key biological processes. The complexity of cancer pathogenesis is best illustrated in the six hallmarks of the cancer: (1) the development of self-sufficient growth signals, (2) the emergence of clones that are resistant to apoptosis, (3) resistance to the antigrowth signals, (4) neo-angiogenesis, (5) the invasion of normal tissue or spread to the distant organs, and (6) limitless replicative potential. It also appears that non-resolving inflammation leads to the dysregulation of immune cell metabolism and subsequent cancer progression. The present article delineates immunometabolic reprogramming as a critical hallmark of cancer by linking chronic inflammation and immunosuppression to cancer growth and metastasis. We propose that targeting tumor immunometabolic reprogramming will lead to the design of novel immunotherapeutic approaches to cancer.
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Affiliation(s)
- Vijay Kumar
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, United States
| | - John H. Stewart
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, United States
- Louisiana State University- Louisiana Children’s Medical Center, Stanley S. Scott, School of Medicine, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, United States
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20
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Singh M, Afonso J, Sharma D, Gupta R, Kumar V, Rani R, Baltazar F, Kumar V. Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics? Semin Cancer Biol 2023; 90:1-14. [PMID: 36706846 DOI: 10.1016/j.semcancer.2023.01.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/23/2023] [Accepted: 01/23/2023] [Indexed: 01/26/2023]
Abstract
As a result of metabolic reprogramming, cancer cells display high rates of glycolysis, causing an excess production of lactate along with an increase in extracellular acidity. Proton-linked monocarboxylate transporters (MCTs) are crucial in the maintenance of this metabolic phenotype, by mediating the proton-coupled lactate flux across cell membranes, also contributing to cancer cell pH regulation. Among the proteins codified by the SLC16 gene family, MCT1 and MCT4 isoforms are the most explored in cancers, being overexpressed in many cancer types, from solid tumours to haematological malignancies. Similarly to what occurs in particular physiological settings, MCT1 and MCT4 are able to mediate lactate shuttles among cancer cells, and also between cancer and stromal cells in the tumour microenvironment. This form of metabolic cooperation is responsible for important cancer aggressiveness features, such as cell proliferation, survival, angiogenesis, migration, invasion, metastasis, immune tolerance and therapy resistance. The growing understanding of MCT functions and regulation is offering a new path to the design of novel inhibitors that can be foreseen in clinical practices. This review provides an overview of the role of MCT isoforms in cancer and summarizes the recent advances in their pharmacological targeting, highlighting the potential of new potent and selective MCT1 and/or MCT4 inhibitors in cancer therapeutics, and anticipating its inclusion in clinical practice.
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Affiliation(s)
- Mamta Singh
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India
| | - Julieta Afonso
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
| | - Dolly Sharma
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India; Amity Institute of Biotechnology, Amity University UP, Sector-125, Noida, India-201313
| | - Rajat Gupta
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India
| | - Vivek Kumar
- Department of Chemistry, DBG College, Sector-18, Panipat, Haryana, India
| | - Reshma Rani
- Drug Discovery, Jubilant Biosys, Greater Noida 201306, UP, India.
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal.
| | - Vinit Kumar
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India.
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Silva A, Cerqueira MC, Rosa B, Sobral C, Pinto-Ribeiro F, Costa MF, Baltazar F, Afonso J. Prognostic Value of Monocarboxylate Transporter 1 Overexpression in Cancer: A Systematic Review. Int J Mol Sci 2023; 24:ijms24065141. [PMID: 36982217 PMCID: PMC10049181 DOI: 10.3390/ijms24065141] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/30/2023] Open
Abstract
Energy production by cancer is driven by accelerated glycolysis, independently of oxygen levels, which results in increased lactate production. Lactate is shuttled to and from cancer cells via monocarboxylate transporters (MCTs). MCT1 works both as an importer and an extruder of lactate, being widely studied in recent years and generally associated with a cancer aggressiveness phenotype. The aim of this systematic review was to assess the prognostic value of MCT1 immunoexpression in different malignancies. Study collection was performed by searching nine different databases (PubMed, EMBASE, ScienceDirect, Scopus, Cochrane Library, Web of Science, OVID, TRIP and PsycINFO), using the keywords "cancer", "Monocarboxylate transporter 1", "SLC16A1" and "prognosis". Results showed that MCT1 is an indicator of poor prognosis and decreased survival for cancer patients in sixteen types of malignancies; associations between the transporter's overexpression and larger tumour sizes, higher disease stage/grade and metastasis occurrence were also frequently observed. Yet, MCT1 overexpression correlated with better outcomes in colorectal cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer patients. These results support the applicability of MCT1 as a biomarker of prognosis, although larger cohorts would be necessary to validate the overall role of MCT1 as an outcome predictor.
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Affiliation(s)
- Ana Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Mónica Costa Cerqueira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Beatriz Rosa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Catarina Sobral
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Filipa Pinto-Ribeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Marta Freitas Costa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Julieta Afonso
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057 Braga, Portugal
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22
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Sennoune SR, Nandagopal GD, Ramachandran S, Mathew M, Sivaprakasam S, Jaramillo-Martinez V, Bhutia YD, Ganapathy V. Potent Inhibition of Macropinocytosis by Niclosamide in Cancer Cells: A Novel Mechanism for the Anticancer Efficacy for the Antihelminthic. Cancers (Basel) 2023; 15:759. [PMID: 36765717 PMCID: PMC9913174 DOI: 10.3390/cancers15030759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/17/2023] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
Niclosamide, a drug used to treat tapeworm infection, possesses anticancer effects by interfering with multiple signaling pathways. Niclosamide also causes intracellular acidification. We have recently discovered that the amino acid transporter SLC38A5, an amino acid-dependent Na+/H+ exchanger, activates macropinocytosis in cancer cells via amino acid-induced intracellular alkalinization. Therefore, we asked whether niclosamide will block basal and SLC38A5-mediated macropinocytosis via intracellular acidification. We monitored macropinocytosis in pancreatic and breast cancer cells using TMR-dextran and the function of SLC38A5 by measuring Li+-stimulated serine uptake. The peptide transporter activity was measured by the uptake of glycylsarcosine. Treatment of the cancer cells with niclosamide caused intracellular acidification. The drug blocked basal and serine-induced macropinocytosis with differential potency, with an EC50 of ~5 μM for the former and ~0.4 μM for the latter. The increased potency for amino acid-mediated macropinocytosis is due to direct inhibition of SLC38A5 by niclosamide in addition to the ability of the drug to cause intracellular acidification. The drug also inhibited the activity of the H+-coupled peptide transporter. We conclude that niclosamide induces nutrient starvation in cancer cells by blocking macropinocytosis, SLC38A5 and the peptide transporter. These studies uncover novel, hitherto unknown, mechanisms for the anticancer efficacy of this antihelminthic.
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Affiliation(s)
- Souad R. Sennoune
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | | | - Sabarish Ramachandran
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Marilyn Mathew
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Sathish Sivaprakasam
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Valeria Jaramillo-Martinez
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Yangzom D. Bhutia
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Understanding the Contribution of Lactate Metabolism in Cancer Progress: A Perspective from Isomers. Cancers (Basel) 2022; 15:cancers15010087. [PMID: 36612084 PMCID: PMC9817756 DOI: 10.3390/cancers15010087] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/13/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Lactate mediates multiple cell-intrinsic effects in cancer metabolism in terms of development, maintenance, and metastasis and is often correlated with poor prognosis. Its functions are undertaken as an energy source for neighboring carcinoma cells and serve as a lactormone for oncogenic signaling pathways. Indeed, two isomers of lactate are produced in the Warburg effect: L-lactate and D-lactate. L-lactate is the main end-production of glycolytic fermentation which catalyzes glucose, and tiny D-lactate is fabricated through the glyoxalase system. Their production inevitably affects cancer development and therapy. Here, we systematically review the mechanisms of lactate isomers production, and highlight emerging evidence of the carcinogenic biological effects of lactate and its isomers in cancer. Accordingly, therapy that targets lactate and its metabolism is a promising approach for anticancer treatment.
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Ying M, Hu X. Tracing the electron flow in redox metabolism: The appropriate distribution of electrons is essential to maintain redox balance in cancer cells. Semin Cancer Biol 2022; 87:32-47. [PMID: 36374644 DOI: 10.1016/j.semcancer.2022.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022]
Abstract
Cancer cells are characterized by sustained proliferation, which requires a huge demand of fuels to support energy production and biosynthesis. Energy is produced by the oxidation of the fuels during catabolism, and biosynthesis is achieved by the reduction of smaller units or precursors. Therefore, the oxidation-reduction (redox) reactions in cancer cells are more active compared to those in the normal counterparts. The higher activity of redox metabolism also induces a more severe oxidative stress, raising the question of how cancer cells maintain the redox balance. In this review, we overview the redox metabolism of cancer cells in an electron-tracing view. The electrons are derived from the nutrients in the tumor microenvironment and released during catabolism. Most of the electrons are transferred to NAD(P) system and then directed to four destinations: energy production, ROS generation, reductive biosynthesis and antioxidant system. The appropriate distribution of these electrons achieved by the function of redox regulation network is essential to maintain redox homeostasis in cancer cells. Interfering with the electron distribution and disrupting redox balance by targeting the redox regulation network may provide therapeutic implications for cancer treatment.
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Affiliation(s)
- Minfeng Ying
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China.
| | - Xun Hu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China.
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25
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Mostafavi S, Zalpoor H, Hassan ZM. The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors. Cell Mol Biol Lett 2022; 27:58. [PMID: 35869449 PMCID: PMC9308248 DOI: 10.1186/s11658-022-00356-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022] Open
Abstract
Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.
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26
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Xu JQ, Fu YL, Zhang J, Zhang KY, Ma J, Tang JY, Zhang ZW, Zhou ZY. Targeting glycolysis in non-small cell lung cancer: Promises and challenges. Front Pharmacol 2022; 13:1037341. [PMID: 36532721 PMCID: PMC9748442 DOI: 10.3389/fphar.2022.1037341] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/04/2022] [Indexed: 08/17/2023] Open
Abstract
Metabolic disturbance, particularly of glucose metabolism, is a hallmark of tumors such as non-small cell lung cancer (NSCLC). Cancer cells tend to reprogram a majority of glucose metabolism reactions into glycolysis, even in oxygen-rich environments. Although glycolysis is not an efficient means of ATP production compared to oxidative phosphorylation, the inhibition of tumor glycolysis directly impedes cell survival and growth. This review focuses on research advances in glycolysis in NSCLC and systematically provides an overview of the key enzymes, biomarkers, non-coding RNAs, and signaling pathways that modulate the glycolysis process and, consequently, tumor growth and metastasis in NSCLC. Current medications, therapeutic approaches, and natural products that affect glycolysis in NSCLC are also summarized. We found that the identification of appropriate targets and biomarkers in glycolysis, specifically for NSCLC treatment, is still a challenge at present. However, LDHB, PDK1, MCT2, GLUT1, and PFKM might be promising targets in the treatment of NSCLC or its specific subtypes, and DPPA4, NQO1, GAPDH/MT-CO1, PGC-1α, OTUB2, ISLR, Barx2, OTUB2, and RFP180 might be prognostic predictors of NSCLC. In addition, natural products may serve as promising therapeutic approaches targeting multiple steps in glycolysis metabolism, since natural products always present multi-target properties. The development of metabolic intervention that targets glycolysis, alone or in combination with current therapy, is a potential therapeutic approach in NSCLC treatment. The aim of this review is to describe research patterns and interests concerning the metabolic treatment of NSCLC.
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Affiliation(s)
- Jia-Qi Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan-Li Fu
- Department of Oncology, Shenzhen (Fu Tian) Hospital, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Jing Zhang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai-Yu Zhang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Ma
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing-Yi Tang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi-Wei Zhang
- Department of Oncology, Shenzhen (Fu Tian) Hospital, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Zhong-Yan Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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27
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Bhatt R, Ravi D, Evens AM, Parekkadan B. Scaffold-mediated switching of lymphoma metabolism in culture. Cancer Metab 2022; 10:15. [PMID: 36224623 PMCID: PMC9559005 DOI: 10.1186/s40170-022-00291-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 09/22/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Diffuse large B cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and accounts for about a third of all NHL cases. A significant proportion (~40%) of treated DLBCL patients develop refractory or relapsed disease due to drug resistance which can be attributed to metabolomic and genetic variations amongst diverse DLBCL subtypes. An assay platform that reproduces metabolic patterns of DLBCL in vivo could serve as a useful model for DLBCL. METHODS This report investigated metabolic functions in 2D and 3D cell cultures using parental and drug-resistant DLBCL cell lines as compared to patient biopsy tissue. RESULTS A 3D culture model controlled the proliferation of parental and drug-resistant DLBCL cell lines, SUDHL-10, SUDHL-10 RR (rituximab resistant), and SUDHL-10 OR (obinutuzumab resistant), as well as retained differential sensitivity to CHOP. The results from metabolic profiling and isotope tracer studies with D-glucose-13C6 indicated metabolic switching in 3D culture when compared with a 2D environment. Analysis of DLBCL patient tumor tissue revealed that the metabolic changes in 3D grown cells were shifted towards that of clinical specimens. CONCLUSION 3D culture restrained DLBCL cell line growth and modulated metabolic pathways that trend towards the biological characteristics of patient tumors. Counter-intuitively, this research thereby contends that 3D matrices can be a tool to control tumor function towards a slower growing and metabolically dormant state that better reflects in vivo tumor physiology.
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Affiliation(s)
- Rachana Bhatt
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Dashnamoorthy Ravi
- Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Andrew M Evens
- Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
- Department of Medicine, Rutgers Biomedical Health Sciences, The State University of New Jersey, New Brunswick, NJ, USA.
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MCT4/Lactate Promotes PD-L1 Glycosylation in Triple-Negative Breast Cancer Cells. JOURNAL OF ONCOLOGY 2022; 2022:3659714. [PMID: 36199799 PMCID: PMC9529401 DOI: 10.1155/2022/3659714] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/30/2022] [Accepted: 08/05/2022] [Indexed: 11/18/2022]
Abstract
Triple-negative breast cancer (TNBC) has the highest percentage of lymphocytic infiltration among breast cancer subtypes, and TNBC patients may benefit from anti-PD-1/PD-L1 immunotherapy. However, some cases whether the immune checkpoint blockade (ICB) shows low targeting efficiency have occurred and effective synergistic targets need to be found, which inspired our exploration of the co-expression analysis of MCT4 (SLC16A3) and PD-L1 (CD274) and their potential regulatory mechanisms. After bioinformatic analysis of the relationship between MCT4 and PD-L1, we validated their positive co-expression relationship in triple-negative breast cancer through multiple immunohistochemical staining (mIHC), CRISPR/Cas9, and lentiviral transduction for MCT4 knockout (sgMCT4/231 KO) or overexpression (pEGFP-N1-MCT4/231). We examined the effect of lactate treatment on PD-L1 expression in triple-negative breast cancer cells by qRT-PCR and Western blot. Combined with our results, we found that MCT4 positively regulated PD-L1 expression through discharging lactate and stabilized PD-L1 through promoting its glycosylation by the classic WNT pathway in MDA-MB-231 cells. More importantly, the high co-expression of MCT4 and PD-L1 appears to predict more effective targets for treating TNBC, which would improve immune checkpoint therapy for TNBC.
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Jiang X, Yan N, Deng D, Yan C. Structural aspects of the glucose and monocarboxylate transporters involved in the Warburg effect. IUBMB Life 2022; 74:1180-1199. [PMID: 36082803 DOI: 10.1002/iub.2668] [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: 05/31/2022] [Accepted: 08/02/2022] [Indexed: 11/11/2022]
Abstract
Cancer cells shift their glucose catabolism from aerobic respiration to lactic fermentation even in the presence of oxygen, and this is known as the "Warburg effect". To accommodate the high glucose demands and to avoid lactate accumulation, the expression levels of human glucose transporters (GLUTs) and human monocarboxylate transporters (MCTs) are elevated to maintain metabolic homeostasis. Therefore, inhibition of GLUTs and/or MCTs provides potential therapeutic strategies for cancer treatment. Here, we summarize recent advances in the structural characterization of GLUTs and MCTs, providing a comprehensive understanding of their transport and inhibition mechanisms to facilitate further development of anticancer therapies.
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Affiliation(s)
- Xin Jiang
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia
| | - Nieng Yan
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA
| | - Dong Deng
- Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China
| | - Chuangye Yan
- Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
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30
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Zuzčák M, Trnka J. Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review). Int J Oncol 2022; 61:93. [PMID: 35730611 PMCID: PMC9256076 DOI: 10.3892/ijo.2022.5383] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/10/2022] [Indexed: 11/28/2022] Open
Abstract
Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched‑chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.
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Affiliation(s)
- Michal Zuzčák
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
- Center for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
| | - Jan Trnka
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
- Center for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
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31
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Liu J, Zhou G, Wang X, Liu D. Metabolic reprogramming consequences of sepsis: adaptations and contradictions. Cell Mol Life Sci 2022; 79:456. [PMID: 35904600 PMCID: PMC9336160 DOI: 10.1007/s00018-022-04490-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 12/19/2022]
Abstract
During sepsis, the importance of alterations in cell metabolism is underappreciated. The cellular metabolism, which has a variable metabolic profile in different cells and disease stages, is largely responsible for the immune imbalance and organ failure associated with sepsis. Metabolic reprogramming, in which glycolysis replaces OXPHOS as the main energy-producing pathway, is both a requirement for immune cell activation and a cause of immunosuppression. Meanwhile, the metabolites produced by OXPHOS and glycolysis can act as signaling molecules to control the immune response during sepsis. Sepsis-induced "energy shortage" leads to stagnated cell function and even organ dysfunction. Metabolic reprogramming can alleviate the energy crisis to some extent, enhance host tolerance to maintain cell survival functions, and ultimately increase the adaptation of cells during sepsis. However, a switch from glycolysis to OXPHOS is essential for restoring cell function. This review summarized the crosstalk between metabolic reprogramming and immune cell activity as well as organ function during sepsis, discussed the benefits and drawbacks of metabolic reprogramming to show the contradictions of metabolic reprogramming during sepsis, and assessed the feasibility of treating sepsis through targeted metabolism. Using metabolic reprogramming to achieve metabolic homeostasis could be a viable therapy option for sepsis.
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Affiliation(s)
- Jingjing Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Gaosheng Zhou
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Xiaoting Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Dawei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
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Zhou X, Kandalai S, Hossain F, Zheng Q. Tumor microbiome metabolism: A game changer in cancer development and therapy. Front Oncol 2022; 12:933407. [PMID: 35936744 PMCID: PMC9351545 DOI: 10.3389/fonc.2022.933407] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Accumulating recent evidence indicates that the human microbiome plays essential roles in pathophysiological states, including cancer. The tumor microbiome, an emerging concept that has not yet been clearly defined, has been proven to influence both cancer development and therapy through complex mechanisms. Small molecule metabolites produced by the tumor microbiome through unique biosynthetic pathways can easily diffuse into tissues and penetrate cell membranes through transporters or free diffusion, thus remodeling the signaling pathways of cancer and immune cells by interacting with biomacromolecules. Targeting tumor microbiome metabolism could offer a novel perspective for not only understanding cancer progression but also developing new strategies for the treatment of multiple cancer types. Here, we summarize recent advances regarding the role the tumor microbiome plays as a game changer in cancer biology. Specifically, the metabolites produced by the tumor microbiome and their potential effects on the cancer development therapy are discussed to understand the importance of the microbial metabolism in the tumor microenvironment. Finally, new anticancer therapeutic strategies that target tumor microbiome metabolism are reviewed and proposed to provide new insights in clinical applications.
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Affiliation(s)
- Xiaozhuang Zhou
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Center for Cancer Metabolism, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Shruthi Kandalai
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Center for Cancer Metabolism, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Farzana Hossain
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Center for Cancer Metabolism, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Qingfei Zheng
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, United States
- Center for Cancer Metabolism, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
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Autoregulation of H +/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production. Br J Cancer 2022; 127:1365-1377. [PMID: 35840734 PMCID: PMC9519749 DOI: 10.1038/s41416-022-01910-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/24/2022] [Accepted: 06/29/2022] [Indexed: 12/02/2022] Open
Abstract
Background Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production. Methods Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; PHLac) and lactic acid production (inferred from H+ and lactate excretion; JHLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype. Results MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce JHLac because of a compensatory increase in the transmembrane [lactate] driving force. JHLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced JHLac but this was via cytoplasmic acidification blocking glycolytic enzymes. Conclusions We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux.
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Tumor Microenvironment: Lactic Acid Promotes Tumor Development. J Immunol Res 2022; 2022:3119375. [PMID: 35733921 PMCID: PMC9207018 DOI: 10.1155/2022/3119375] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/19/2022] [Indexed: 12/17/2022] Open
Abstract
Lactic acid is a "metabolic waste" product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells' effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.
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Longhitano L, Vicario N, Tibullo D, Giallongo C, Broggi G, Caltabiano R, Barbagallo GMV, Altieri R, Baghini M, Di Rosa M, Parenti R, Giordano A, Mione MC, Li Volti G. Lactate Induces the Expressions of MCT1 and HCAR1 to Promote Tumor Growth and Progression in Glioblastoma. Front Oncol 2022; 12:871798. [PMID: 35574309 PMCID: PMC9097945 DOI: 10.3389/fonc.2022.871798] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/23/2022] [Indexed: 12/04/2022] Open
Abstract
The tumor microenvironment (TME) plays a pivotal role in establishing malignancy, and it is associated with high glycolytic metabolism and lactate release through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signaling molecule through its receptor hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), thus functioning as a paracrine and autocrine signaling molecule. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an in vitro and in vivo model. The cell proliferation, migration, and clonogenicity were tested in vitro in three different human GBM cell lines. The expressions of MCT1, MCT4, and HCAR1 were evaluated both in vitro and in a zebrafish GBM model. The results were further validated in patient-derived GBM biopsies. Our results showed that lactate significantly increased the cell proliferation, migration, and colony formation capacity of GBM cells, both in vitro and in vivo. We also showed that lactate increased the expressions of MCT1 and HCAR1. Moreover, lactate modulated the epithelial-mesenchymal transition protein markers E-cadherin and β-catenin. Interestingly, lactate induced mitochondrial mass and the OXPHOS gene, suggesting improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-dihydroxybenzoic acid, a known agonist of HCAR1. Consistently, the GBM zebrafish model exhibited an altered metabolism and increased expressions of MCT1 and HCAR1, leading to high levels of extracellular lactate and, thus, supporting tumor cell proliferation. Our data from human GBM biopsies also showed that, in high proliferative GBM biopsies, Ki67-positive cells expressed significantly higher levels of MCT1 compared to low proliferative GBM cells. In conclusion, our data suggest that lactate and its transporter and receptor play a major role in GBM proliferation and migration, thus representing a potential target for new therapeutic strategies to counteract tumor progression and recurrence.
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Affiliation(s)
- Lucia Longhitano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Nunzio Vicario
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Daniele Tibullo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Cesarina Giallongo
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Catania, Italy
| | - Giuseppe Broggi
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Catania, Italy
| | - Rosario Caltabiano
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Catania, Italy
| | - Giuseppe Maria Vincenzo Barbagallo
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia” Neurological Surgery, Policlinico “G. Rodolico-San Marco” University Hospital, University of Catania, Catania, Italy
- Interdisciplinary Research Center on Brain Tumors Diagnosis and Treatment, University of Catania, Catania, Italy
| | - Roberto Altieri
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia” Neurological Surgery, Policlinico “G. Rodolico-San Marco” University Hospital, University of Catania, Catania, Italy
- Interdisciplinary Research Center on Brain Tumors Diagnosis and Treatment, University of Catania, Catania, Italy
| | - Marta Baghini
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Michelino Di Rosa
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine and Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, United States
| | - Maria Caterina Mione
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Transcriptomic Biomarker Signatures for Discrimination of Oral Cancer Surgical Margins. Biomolecules 2022; 12:biom12030464. [PMID: 35327656 PMCID: PMC8946245 DOI: 10.3390/biom12030464] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/01/2022] [Accepted: 03/11/2022] [Indexed: 02/01/2023] Open
Abstract
Relapse after surgery for oral squamous cell carcinoma (OSCC) contributes significantly to morbidity, mortality and poor outcomes. The current histopathological diagnostic techniques are insufficiently sensitive for the detection of oral cancer and minimal residual disease in surgical margins. We used whole-transcriptome gene expression and small noncoding RNA profiles from tumour, close margin and distant margin biopsies from 18 patients undergoing surgical resection for OSCC. By applying multivariate regression algorithms (sPLS-DA) suitable for higher dimension data, we objectively identified biomarker signatures for tumour and marginal tissue zones. We were able to define molecular signatures that discriminated tumours from the marginal zones and between the close and distant margins. These signatures included genes not previously associated with OSCC, such as MAMDC2, SYNPO2 and ARMH4. For discrimination of the normal and tumour sampling zones, we were able to derive an effective gene-based classifying model for molecular abnormality based on a panel of eight genes (MMP1, MMP12, MYO1B, TNFRSF12A, WDR66, LAMC2, SLC16A1 and PLAU). We demonstrated the classification performance of these gene signatures in an independent validation dataset of OSCC tumour and marginal gene expression profiles. These biomarker signatures may contribute to the earlier detection of tumour cells and complement existing surgical and histopathological techniques used to determine clear surgical margins.
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Kooshki L, Mahdavi P, Fakhri S, Akkol EK, Khan H. Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer. Biofactors 2022; 48:359-383. [PMID: 34724274 DOI: 10.1002/biof.1799] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022]
Abstract
Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.
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Affiliation(s)
- Leila Kooshki
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parisa Mahdavi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
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Mafi S, Mansoori B, Taeb S, Sadeghi H, Abbasi R, Cho WC, Rostamzadeh D. mTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment. Front Immunol 2022; 12:774103. [PMID: 35250965 PMCID: PMC8894239 DOI: 10.3389/fimmu.2021.774103] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 12/14/2021] [Indexed: 12/17/2022] Open
Abstract
The mechanistic/mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, which plays a pivotal role in regulating numerous cellular functions including cell growth, proliferation, survival, and metabolism by integrating a variety of extracellular and intracellular signals in the tumor microenvironment (TME). Dysregulation of the mTOR pathway is frequently reported in many types of human tumors, and targeting the PI3K/Akt/mTOR signaling pathway has been considered an attractive potential therapeutic target in cancer. The PI3K/Akt/mTOR signaling transduction pathway is important not only in the development and progression of cancers but also for its critical regulatory role in the tumor microenvironment. Immunologically, mTOR is emerging as a key regulator of immune responses. The mTOR signaling pathway plays an essential regulatory role in the differentiation and function of both innate and adaptive immune cells. Considering the central role of mTOR in metabolic and translational reprogramming, it can affect tumor-associated immune cells to undergo phenotypic and functional reprogramming in TME. The mTOR-mediated inflammatory response can also promote the recruitment of immune cells to TME, resulting in exerting the anti-tumor functions or promoting cancer cell growth, progression, and metastasis. Thus, deregulated mTOR signaling in cancer can modulate the TME, thereby affecting the tumor immune microenvironment. Here, we review the current knowledge regarding the crucial role of the PI3K/Akt/mTOR pathway in controlling and shaping the immune responses in TME.
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Affiliation(s)
- Sahar Mafi
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Behzad Mansoori
- The Wistar Institute, Molecular & Cellular Oncogenesis Program, Philadelphia, PA, United States
| | - Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
- Medical Biotechnology Research Center, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Hossein Sadeghi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Reza Abbasi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong SAR, China
| | - Davoud Rostamzadeh
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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Yuan C, Zhang J, Lou J, Wang S, Jiang Y, Wu F, Wang S. Comprehensive Analysis of Monocarboxylate Transporter 4 (MCT4) expression in breast cancer prognosis and immune infiltration via integrated bioinformatics analysis. Bioengineered 2021; 12:3850-3863. [PMID: 34269158 PMCID: PMC8806482 DOI: 10.1080/21655979.2021.1951928] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 11/06/2022] Open
Abstract
Lactate blunts the anticancer immune response in breast cancer (BC). However, little is known about the exact effect of lactate transporters such as monocarboxylate transporter 4 (MCT4) on immunotherapy. In this study, we investigated the expression status and prognostic value of MCT4 in BC through large-scale transcriptome data. Our results showed that MCT4 was overexpressed in BC, particularly in the basal-like molecular subtype. Overexpression of MCT4 was significantly correlated with high BC lesion grade and poor prognosis. Enrichment analysis indicated that the MCT4-related genes were involved in immune- and metabolism-related bioprocesses, such as myeloid leukocyte activation, the adaptive immune system, and catabolic process. We also found that the expression of MCT4 in BC lesions was associated with immune cell infiltration and glycolytic rate-limiting enzymes like pyruvate kinase M2 (PKM2) and hexokinases-3 (HK3). Our observations indicate that MCT4 may play a pivotal role in the maintenance of the tumor immune microenvironment (TIME) through metabolic reprogramming. The enzymes of the glycolysis pathway (MCT4, PKM2, and HK3) may thus serve as new targets to modulate the TIME and enhance immunotherapy efficiency.[Figure: see text].
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Affiliation(s)
- Chen Yuan
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Zhang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianjuan Lou
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Siqi Wang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yanni Jiang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feiyun Wu
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shouju Wang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Manoharan I, Prasad PD, Thangaraju M, Manicassamy S. Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages. Front Immunol 2021; 12:691134. [PMID: 34394085 PMCID: PMC8358770 DOI: 10.3389/fimmu.2021.691134] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/14/2021] [Indexed: 12/28/2022] Open
Abstract
For decades, lactate has been considered an innocuous bystander metabolite of cellular metabolism. However, emerging studies show that lactate acts as a complex immunomodulatory molecule that controls innate and adaptive immune cells’ effector functions. Thus, recent advances point to lactate as an essential and novel signaling molecule that shapes innate and adaptive immune responses in the intestine and systemic sites. Here, we review these recent advances in the context of the pleiotropic effects of lactate in regulating diverse functions of immune cells in the tissue microenvironment and under pathological conditions.
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Affiliation(s)
- Indumathi Manoharan
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Puttur D Prasad
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Santhakumar Manicassamy
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States
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Matheux A, Gassiot M, Fromont G, Leenhardt F, Boulahtouf A, Fabbrizio E, Marchive C, Garcin A, Agherbi H, Combès E, Evrard A, Houédé N, Balaguer P, Gongora C, Mbatchi LC, Pourquier P. PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1. Cancers (Basel) 2021; 13:cancers13143635. [PMID: 34298852 PMCID: PMC8305337 DOI: 10.3390/cancers13143635] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 01/12/2023] Open
Abstract
Simple Summary Many kinase inhibitors have been tested as potential alternatives for the treatment of castration-resistant prostate cancers. However, none of these clinical trials led to drug approval despite interesting responses. Our study reveals that genes involved in drug metabolism and their master regulator PXR (Pregnane X Receptor) could be responsible, at least in part, for these disappointing results as they can modulate tumor cell response to specific kinase inhibitors. We found that stable expression of PXR sensitized prostate cancer cells to erlotinib, dabrafenib, and afatinib, while it rendered cells resistant to dasatinib and had no effect for other inhibitors tested. We also report for the first time that sensitization to afatinib is due to an alteration in drug transport that involves the SLC16A1 monocarboxylate transporter. Together, our results further indicate that PXR might be considered as a biomarker of response to kinase inhibitors in castration-resistant prostate cancers. Abstract Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.
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Affiliation(s)
- Alice Matheux
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
- Laboratoire de Biochimie et Biologie Moléculaire, CHU Carémeau, F-30029 Nîmes, France
| | - Matthieu Gassiot
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Gaëlle Fromont
- Département de Pathologie, CHU de Tours, Université François Rabelais, Inserm UMR 1069, F-37044 Tours, France;
| | - Fanny Leenhardt
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
- Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, F-34090 Montpellier, France
| | - Abdelhay Boulahtouf
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Eric Fabbrizio
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Candice Marchive
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Aurélie Garcin
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Hanane Agherbi
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Eve Combès
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Alexandre Evrard
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
- Laboratoire de Biochimie et Biologie Moléculaire, CHU Carémeau, F-30029 Nîmes, France
- Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, F-34090 Montpellier, France
| | - Nadine Houédé
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
- Département d’Oncologie Médicale, Institut de Cancérologie du Gard—CHU Carémeau, F-30029 Nîmes, France
| | - Patrick Balaguer
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Céline Gongora
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
| | - Litaty C. Mbatchi
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
- Laboratoire de Biochimie et Biologie Moléculaire, CHU Carémeau, F-30029 Nîmes, France
- Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, F-34090 Montpellier, France
| | - Philippe Pourquier
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; (A.M.); (M.G.); (F.L.); (A.B.); (E.F.); (C.M.); (A.G.); (H.A.); (E.C.); (A.E.); (N.H.); (P.B.); (C.G.); (L.C.M.)
- Correspondence: ; Tel.: +33-4-66-68-32-31
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Chandel V, Maru S, Kumar A, Kumar A, Sharma A, Rathi B, Kumar D. Role of monocarboxylate transporters in head and neck squamous cell carcinoma. Life Sci 2021; 279:119709. [PMID: 34102188 DOI: 10.1016/j.lfs.2021.119709] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/29/2021] [Accepted: 05/29/2021] [Indexed: 11/24/2022]
Abstract
Head and Neck tumors are metabolically highly altered solid tumors. Head and Neck cancer cells may utilise different metabolic pathways for energy production. Whereas, glycolysis is the major source coupled with oxidative phosphorylation in a metabolic symbiosis manner that results in the proliferation and metastasis in Head and Neck Cancer. The monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 are responsible for transporting monocarboxylates such as l-lactate and pyruvate, and ketone bodies across the plasma membrane. Additionally, MCTs mediate absorption and distribution of monocarboxylates across the cell membrane. Head and Neck cancer cells are highly glycolytic in nature and generate significant amount of lactic acid in the extracellular environment. In such condition, MCTs play a critical role in the regulation of pH, and lactate shuttle maintenance. The intracellular lactate accumulation is harmful for the cells since it drastically lowers the intracellular pH. MCTs facilitate the export of lactate out of the cell. The lactate export mediated by MCTs is crucial for the cancer cells survival. Therefore, targeting MCTs is important and could be a potential therapeutic approach to control growth of the tumor.
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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
| | - Saurabh Maru
- School of Pharmacy and Technology Management, SVKM'S NMIMS Deemed to be University, Shirpur, Maharashtra, India
| | - Arun Kumar
- Mahavir Cancer Institute & Research Centre, Phulwarisharif, Patna 801505, Bihar, India
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Bhopal, Saket Nagar, Bhopal 462 020, Madhya Pradesh, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi 110029, Bharat, India
| | - Brijesh Rathi
- Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, India; Laboratory of Computational Modelling of Drugs, South Ural State University, Chelyabinsk, Russia
| | - 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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Reiter RJ, Sharma R, Rodriguez C, Martin V, Rosales-Corral S, Zuccari DAPDC, Chuffa LGDA. Part-time cancers and role of melatonin in determining their metabolic phenotype. Life Sci 2021; 278:119597. [PMID: 33974932 DOI: 10.1016/j.lfs.2021.119597] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/26/2021] [Accepted: 05/03/2021] [Indexed: 12/14/2022]
Abstract
This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA.
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Carmen Rodriguez
- Departamento de Morfologia y Biologia Celular, Facultad de Medicina, Oviedo, 33006, Spain
| | - Vanesa Martin
- Departamento de Morfologia y Biologia Celular, Facultad de Medicina, Oviedo, 33006, Spain
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara CP 45150, Mexico
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Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences. Int J Mol Sci 2021; 22:ijms22073775. [PMID: 33917351 PMCID: PMC8038661 DOI: 10.3390/ijms22073775] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.
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45
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Li M, Long X, Wan H, Yin M, Yang B, Zhang F, Guo X. Monocarboxylate transporter 1 promotes proliferation and invasion of renal cancer cells by mediating acetate transport. Cell Biol Int 2021; 45:1278-1287. [PMID: 33559958 DOI: 10.1002/cbin.11571] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/21/2021] [Accepted: 02/07/2021] [Indexed: 12/24/2022]
Abstract
One hallmark of renal cell carcinoma (RCC) is metabolic reprogramming, which involves elevation of glycolysis and upregulation of lipid metabolism. However, the mechanism of metabolic reprogramming is incompletely understood. Monocarboxylate transporter 1 (MCT1) promotes transport for lactate and pyruvate, which are crucial for cell metabolism. The aim of present study was to investigate the function of MCT1 on RCC development and its mechanism on metabolic reprogramming. The results showed that MCT1 messenger RNA and protein levels significantly increased in cancer tissues of ccRCC compared to normal tissue. MCT1 was further found to mainly located in the cell membrane of RCC. The knockdown of MCT1 by RNAi significantly inhibited proliferation and migration of 786-O and ACHN cells. MCT1 also induced the expressions of proliferation marker Ki-67 and invasion marker SNAI1. Moreover, we also showed that acetate treatment could upregulate the expression of MCT1, but not other MCT isoforms. On the other hand, MCT1 was involved in acetate transport and intracellular histone acetylation. In summary, this study revealed that MCT1 is abnormally high in ccRCC and promotes cancer development. The regulatory effect of MCT1 on cell proliferation and invasion maybe mediated by acetate transport.
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Affiliation(s)
- Minghua Li
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Xia Long
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Huijuan Wan
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Meijun Yin
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Bo Yang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong, China
| | - Fangting Zhang
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Xiaoqiang Guo
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.,Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong, China.,Xiaobei Medical Research Institute, Department of Physical Education, Shijiazhuang Vocational College of Technology, Shijiazhuang, Hebei, China
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Venkateswaran G, Dedhar S. Interplay of Carbonic Anhydrase IX With Amino Acid and Acid/Base Transporters in the Hypoxic Tumor Microenvironment. Front Cell Dev Biol 2020; 8:602668. [PMID: 33240897 PMCID: PMC7680889 DOI: 10.3389/fcell.2020.602668] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 10/09/2020] [Indexed: 01/13/2023] Open
Abstract
Solid tumors are challenged with a hypoxic and nutrient-deprived microenvironment. Hence, hypoxic tumor cells coordinatively increase the expression of nutrient transporters and pH regulators to adapt and meet their bioenergetic and biosynthetic demands. Carbonic Anhydrase IX (CAIX) is a membrane-bound enzyme that plays a vital role in pH regulation in the tumor microenvironment (TME). Numerous studies have established the importance of CAIX in mediating tumor progression and metastasis. To understand the mechanism of CAIX in mediating tumor progression, we performed an unbiased proteomic screen to identify the potential interactors of CAIX in the TME using the proximity-dependent biotin identification (BioID) technique. In this review, we focus on the interactors from this BioID screen that are crucial for nutrient and metabolite transport in the TME. We discuss the role of transport metabolon comprising CAIX and bicarbonate transporters in regulating intra- and extracellular pH of the tumor. We also discuss the role of amino acid transporters that are high confidence interactors of CAIX, in optimizing favorable metabolic state for tumor progression, and give our perspective on the coordinative interplay of CAIX with the amino acid transporters in the hypoxic TME.
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Affiliation(s)
- Geetha Venkateswaran
- Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Interdisciplinary Oncology Program, The University of British Columbia, Vancouver, BC, Canada
| | - Shoukat Dedhar
- Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Interdisciplinary Oncology Program, The University of British Columbia, Vancouver, BC, Canada.,Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
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