Role of monocarboxylate transporters in human cancers: state of the art

Abstract

Monocarboxylate transporters (MCTs) belong to the SLC16 gene family, presently composed by 14 members. MCT1-MCT4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. The role of MCTs in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is still far from understood. Most solid tumors are known to rely on glycolysis for energy production and this activity leads to production of important amounts of lactate, which are exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, MCTs will play a dual role in the maintenance of the hyper-glycolytic acid-resistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the co-transport of protons. Thus, they constitute attractive targets for cancer therapy, which have been little explored. Here we review the literature on the role of MCTs in solid tumors in different locations, such as colon, central nervous system, breast, lung, gynecologic tract, prostate, stomach, however, there are many conflicting results and in most cases there are no functional studies showing the dependence of the tumors on MCT expression and activity. Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness.

Cancer metabolism in space and time: Beyond the Warburg effect

“…Lac tate ex changes have been sub stan ti ated in dif fer ent types of can cers [72,83], in di cat ing that they con sti tute a gen eral meta bolic adap ta tion to harsh mi croen vi ron men tal con di tions. The ox ida tive use of lac tate is not unique to can cer cells and can be found for ex am…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…Accordingly, aberrant expression of MCT1, MCT2, and/or MCT4 has been demonstrated e.g., in colon cancer, glioblastoma, breast cancer, prostate cancer, pancreatic cancer, or clear cell renal cell carcinoma 29, 30. A comprehensive overview of aberrant MCT1, MCT2, and MCT4 expression in different cancer entities is provided by Pinheiro et al 31. With this important impact on lactate metabolism in tumor cells, MCT1, MCT2, and MCT4 have been proposed as diagnostic biomarkers or prognostic factors for cancer outcome and survival.…”

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

“…In human mammary cancer, increased NHE1 expression was found in DCIS compared with normal tissue, yet with no correlation between the localization of the hypoxia-responsive glucose transporter GLUT1 and NHE1 [81], hence the possible link of NHE1 expression in cancer to hypoxia requires further investigations. MCTs contribute to the maintenance of cancer cell growth by exporting lactate and thus allowing a continuous high level of glycolysis [82]. In addition, MCT activity contributes to acid extrusion by obligatory symport of H þ [82].…”

“…MCTs contribute to the maintenance of cancer cell growth by exporting lactate and thus allowing a continuous high level of glycolysis [82]. In addition, MCT activity contributes to acid extrusion by obligatory symport of H þ [82]. MCT4, but not MCT1, is upregulated by hypoxia in a manner dependent on HIF-1, owing to HREs in the MCT4 promoter [16].…”