The relationship between monocarboxylate transporter and tumor metabolism
1，2Chen Zhe-wen，3Zhang Jie4， Wang Zheng-ping，5Song Meng-meng，6Zhang Qi-yu， 7Miao Ming-yong，1Shi Han-ping
1Department of Clinical Nutrition/Gastrointestinal Surgery， Beijing Shijitan Hospital， Capital Medical University， Beijing 100038， China；2The Second Affiliated Hospital， Wenzhou Medical University， Wenzhou 325000， Zhejiang， China； 3The Affiliated Huai'an Hospital of Xuzhou Medical University， Huai'an 223002，Jiangsu， China； 4Institute of BioPharmaccutical Research， Liaocheng University， Liaochen 252059， Shandong， China；5Zhengzhou University， Zhengzhou 450000， Henan， China；6The First Affiliated Hospital， Wenzhou Medical University， Wenzhou 325000， Zhejiang， China；7Department of Biochemistry and Molecular Biology， The College of Basic Medical Sciences， The Second Military Medical University， Shanghai 200433， China
Abstract：Monocarboxylate transporters (MCTs) are important transmembrane transporters responsible for monocarboxylate metabolites such as pyruvate， lactate， ketone bodies. They promote nutrient absorption of these substances and maintain the metabolic balance of cells. The expression of MCT in tumors is significantly up-regulated， which is closely related to glucose metabolism， lipid metabolism， energy metabolism and the formation of tumor microenvironment， and plays an essential role in maintaining the high glycolytic state of tumor cells. In some tumors， lactic acid is produced by glycolytic cells in the hypoxic region， excreted into the tumor microenvironment by MCT4， and then taken up by peripheral oxidized cells expressing MCT1， finally enters the TCA cycle and becomes a fuel for respiration. Pyruvate is also effluxed out of tumor cells by MCT1 and MCT2， while pyruvate in the tumor microenvironment promotes lung metastasis of breast cancer. At the same time， MCT promotes the formation of acidic tumor microenvironment， which is not only conducive to the growth， proliferation and metastasis of tumors， but also causes the death of normal cells around the tumor. The immunosuppression of tumors is also related to this. A number of studies have proved that the high expression of MCT1 and MCT4 is positively correlated with tumor malignancy and prognosis. Inhibition of MCT expression influences tumor growth， proliferation and metastasis， which provides potential therapeutic targets for targeted therapy. Currently MCT inhibitors such as CHC， AR-C155858 and AZD3965 are lack of selectivity for MCT subtypes， but have shown good therapeutic effects. While developing new MCT inhibitors， exploring strategies for joint application with traditional tumor therapies has a good clinical application prospect.
陈哲文，张杰，王正平，宋蒙蒙，张启瑜，缪明永，石汉平. 单羧酸转运载体与肿瘤代谢的关系[J]. 肿瘤代谢与营养电子杂志, 2019, 6(2): 266-271.
Chen Zhe-wen，Zhang Jie， Wang Zheng-ping，Song Meng-meng，Zhang Qi-yu， Miao Ming-yong，Shi Han-ping. The relationship between monocarboxylate transporter and tumor metabolism. Electron J Metab Nutr Cancer, 2019, 6(2): 266-271.
1.Halestrap AP. The monocarboxylate transporter family-Structure and functional characterization. IUBMB Life. 2012;64(1):1-9.
2.Halestrap AP. The SLC16 gene family-structure, role and regulation in health and disease. Mol Aspects Med. 2013;34(2-3):337-349.
3.Fisel P, Schaeffeler E, Schwab M. Clinical and functional relevance of the monocarboxylate transporter family in disease pathophysiology and drug therapy. Clin Transl Sci. 2018;11(4):352-364.
4.Murakami Y, Kohyama N, Kobayashi Y, et al. Functional characterization of human monocarboxylate transporter 6 (SLC16A5). Drug Metab Dispos. 2005;33(12):1845-1851.
5.Suzuki A, Stern SA, Bozdagi O, et al. Astrocyte-neuron lactate transport is required for long-term memory formation.Cell. 2011;144 (5):810-823.
6.Halestrap AP, Wilson MC. The monocarboxylate transporter family-role and regulation. IUBMB Life. 2012;64(2):109-119.
7.Li X, Yu X, Dai D, et al. The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters. Oncotarget. 2016;7(17):23141-23155.
8.Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703-707.
9.Afonso J, Pinto T, Simes-Sousa S, et al. Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma-MCT1 as potential target in diffuse large B cell lymphoma.Cell Oncol (Dordr). 2019;doi: 101007/s13402-019-00426-2.
10.Faubert B, Li KY, Cai L, et al. Lactate metabolism in human lung tumors. Cell. 2017;171(2):358-371.e9.
11.Sonveaux P, Végran F, Schroeder T, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118(12):3930-3942.
12.Wilde L, Roche M, Domingo-Vidal M, et al. Metabolic coupling and the reverse warburg effect in cancer: Implications for novel biomarker and anticancer agent development.Semin Oncol. 2017;44(3):198-203.
13.Hong CS, Graham NA, Gu W, et al. MCT1 Modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4.Cell Rep. 2016;14(7):1590-1601.
14.Elia I, Rossi M, Stegen S, et al. Breast cancer cells rely on environmental pyruvate to shape the metastatic niche. Nature. 2019;568(7750):117-121.
15.Huang, Li T, Wang L, et al. Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress.Cell Res. 2016;26(10):1112-1130.
16.Zhang J, Jia PP, Liu QL, et al. Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo.J Lipid Res. 2018;59(4):625-634.
17.Doherty JR, Yang C, Scott KE, et al. Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res. 2014;74(3):908-920.
18.Asgharzadeh MR, Barar J, Pourseif MM, et al. Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy.Bioimpacts. 2017;7(2):115-133.
19.Peppicelli S, Andreucci E, Ruzzolini J, et al. The acidic microenvironment as a possible niche of dormant tumor cells.Cell Mol Life Sci. 2017;74(15):2761-2771.
20.Silva LS, Poschet G, Nonnenmacher Y, et al. Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype. EMBO Rep. 2017;18(12):2172-2185.
21.Kim Y, Choi JW, Lee JH, et al. Expression of lactate/H+ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.Hum Pathol. 2015;46(1):104-112.
22.Cao YW, Liu Y, Dong Z, et al. Monocarboxylate transporters MCT1 and MCT4 are independent prognostic biomarkers for the survival of patients with clear cell renal cell carcinoma and those receiving therapy targeting angiogenesis. Urol Oncol. 2018;36(6):311.e15 -311.e25.
23.Alves VA, Pinheiro C, Morais-Santos F, et al. Characterization of monocarboxylate transporter activity in hepatocellular carcinoma. World J Gastroenterol. 2014;20(33):11780-11787.
24.Ohno A, Yorita K, Haruyama Y, et al. Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma. Liver Int. 2014;34(6):942-952.
25.Kong SC, Nhr-Nielsen A, Zeeberg K, et al.Monocarboxylate transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells. Pancreas. 2016;45(7):1036-1047.
26.Pinheiro C, Albergaria A, Paredes J, et al. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology. 2010;56(7):860-867.
27.de Oliveira AT, Pinheiro C, Longatto-Filho A, et al. Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs).J Bioenerg Biomembr. 2012;44(1):171-178.
28.Latif A, Chadwick AL, Kitson SJ, et al. Monocarboxylate transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer. BMC Clin Pathol. 2017;17:27.
29.Pinheiro C, Longatto-Filho A, Pereira SM, et al. Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma. Dis Markers. 2009;26(3):97-103.
30.Zhao Z, Wu MS, Zou C, et al. Down regulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway. Cancer Lett. 2014;342(1):150-158.
31.Pinheiro C, Penna V, Morais-Santos F, et al. Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization. J Transl Med. 2014;12(1):118.
32.Huhta H, Helminen O, Palomki S, et al. Intratumoral lactate metabolism in Barretts esophagus and adenocarcinoma. Oncotarget. 2017;8(14):22894-22902.
33.Park SJ, Smith CP, Wilbur RR, et al. An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications.Am J Cancer Res. 2018;8(10):1967-1976.
34.Pinheiro C, Reis RM, Ricardo S, et al. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44.J Biomed Biotechnol. 2010;2010:427694.
35.Eilertsen M, Andersen S, Al-Saad S, et al. Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival.PLoS One. 2014;9(9):e105038.
36.Pérez-Escuredo J, Van Hée VF, Sboarina M, et al. Monocarboxylate transporters in the brain and in cancer.Biochim Biophys Acta. 2016;1863(10):2481-2497.
37.Curtis NJ, Mooney L, Hopcroft L, et al. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitts lymphoma anti-tumor activity. Oncotarget. 2017;8(41):69219-69236.
38.Bola BM, Chadwick AL, Michopoulos F, et al. Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport. Mol Cancer Ther. 2014;13(12):2805-2816.
39.Corbet C, Bastien E, Draoui N, et al. Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects. Nat Commun. 2018;9(1):1208.
40.Benjamin D, Colombi M, Hindupur SK, et al. Syrosingopine sensitizes cancer cells to killing by metformin.Sci Adv. 2016;2(12):e1601756.
41.Benjamin D, Robay D, Hindupur SK, et al. Dual Inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells.Cell Rep. 2018; 25(11):3047-3058.e4.
