Abstract
Proton-coupled monocarboxylate transporters (MCTs), representing the first four isoforms of the SLC16A gene family, mainly participate in the transport of lactate, pyruvate, and other monocarboxylates. Cancer cells exhibit a metabolic shift from oxidative metabolism to an enhanced glycolytic phenotype, leading to a higher production of lactate in the cytoplasm. Excessive accumulation of lactate threatens the survival of cancer cells, and the overexpression of proton-coupled MCTs observed in multiple types of cancer facilitates enhanced export of lactate from highly glycolytic cancer cells. Proton-coupled MCTs not only play critical roles in the metabolic symbiosis between hypoxic and normoxic cancer cells within tumors but also mediate metabolic interaction between cancer cells and cancer-associated stromal cells. Of the four proton-coupled MCTs, MCT1 and MCT4 are the predominantly expressed isoforms in cancer and have been identified as potential therapeutic targets in cancer. Therefore, in this review, we primarily focus on the roles of MCT1 and MCT4 in the metabolic reprogramming of cancer cells under hypoxic and nutrient-deprived conditions. Additionally, we discuss how MCT1 and MCT4 serve as metabolic links between cancer cells and cancer-associated stromal cells via transport of crucial monocarboxylates, as well as present emerging opportunities and challenges in targeting MCT1 and MCT4 for cancer treatment.
Highlights
Monocarboxylate transporters (MCTs) belong to the SLC16A gene family and comprise 14 members
In tumor-stroma contact models, a symbiotic relationship termed as the reverse Warburg effect has been established in which stromal cells are induced by oxidative cancer cells to undergo a glycolytic switch and MCT4 upregulation, and metabolites including lactate and pyruvate are imported into the cancer cells for oxidative phosphorylation (OXPHOS) in a MCT1-dependent manner
MCT1/4-mediated transport of metabolites such as lactate and pyruvate plays a decisive role in metabolic symbiosis between hypoxic and normoxic cancer cells within tumors and links crosstalk between cancer cells and stromal cells including immune cells, endothelial cells and fibroblasts
Summary
Monocarboxylate transporters (MCTs) belong to the SLC16A gene family and comprise 14 members. Tumor cell-derived lactate can enter the neighboring normoxic cancer cells via MCT1 for OXPHOS, sparing glucose for glycolytic cancer cells (Sonveaux et al, 2008; Doherty and Cleveland, 2013) This form of metabolic symbiosis illustrates how the apparent waste product from hypoxic tumor cells may be exploited by oxidative tumor cells to sustain their energy production under nutrientdeprived condition. Infusing tumors with 13Clabeled lactate resulted in higher amounts of labeled metabolites TCA cycle metabolites compared to infusion with 13C-labeled glucose (Faubert et al, 2017) These findings highlight that the lactate transport between hypoxic and normoxic tumor cells mediated by MCT1/4 may be crucial for energy production, tumor proliferation and invasion. Targeting the metabolic interplay within the TME is indispensable for developing new interventions for cancer management
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