Proton-coupled monocarboxylate transporters in cancer: From metabolic crosstalk, immunosuppression and anti-apoptosis to clinical applications

Abstract

The Warburg effect is known as the hyperactive glycolysis that provides the energy needed for rapid growth and proliferation in most tumor cells even under the condition of sufficient oxygen. This metabolic pattern can lead to a large accumulation of lactic acid and intracellular acidification, which can affect the growth of tumor cells and lead to cell death. Proton-coupled monocarboxylate transporters (MCTs) belong to the SLC16A gene family, which consists of 14 members. MCT1-4 promotes the passive transport of monocarboxylate (e.g., lactate, pyruvate, and ketone bodies) and proton transport across membranes. MCT1-4-mediated lactate shuttling between glycolytic tumor cells or cancer-associated fibroblasts and oxidative tumor cells plays an important role in the metabolic reprogramming of energy, lipids, and amino acids and maintains the survival of tumor cells. In addition, MCT-mediated lactate signaling can promote tumor angiogenesis, immune suppression and multidrug resistance, migration and metastasis, and ferroptosis resistance and autophagy, which is conducive to the development of tumor cells and avoid death. Although there are certain challenges, the study of targeted drugs against these transporters shows great promise and may form new anticancer treatment options.

Keywords: MCT inhibitors; angiogenesis; autophagy; lactate; metastasis; monocarboxylate transporters; tumor metabolism; tumor microenvironment.

FIGURE 1

Model depicting MCT-mediated lactate transport in cancer: metabolic crosstalk, immunosuppression, tumor angiogenesis and anti-apoptosis. (A) MCT1-4-mediated lactate shuttling between glycolytic tumor cells and oxidized tumor cells Firstly, glycolytic tumor cells and stromal cells in the hypoxic region produce lactate and hydrogen ions by glycolysis, which are excreted into the tumor microenvironment by MCT4, and then taken up by oxidized tumor cells expressing MCT1. It is reduced to pyruvate and NANPH by LDH and enters the TCA. In addition, MCT1-mediated lactate intake can lead to the disruption of AMP/ATP balance and the inactivation of AMPK, and up-regulate the expression of SCD1 through the AMPK-SREBP1 pathway to promote the biosynthesis of MUFAs. MUFAs are substrates for the synthesis of various lipids. Finally, lactate ingestion via MCT1 stimulates glutamine uptake and catabolism by inhibiting PHD, stabilizing HIF-2α, transactivating c-Myc, and upregulating ASCT2 and GLS1 expression. (B) MCT-mediated lactate transport inhibits immune cells MCT-mediated lactate transport affects the maturation of DCS by reducing the efficiency of NF-κB binding to DNA, promotes the differentiation of peripheral blood mononuclear cells in MDSCs, and reduces the activity of NK cells. MCT-mediated lactate intake promotes the translocation of activated TNF-1 to the nucleus and up-regulates the expression of PD-1 in Tregs, but inhibits in effector T cells. PD-1 blockade activates PD-1-expressing Treg cells and inhibits effector T cells. In addition, lactate enters neutrophils through MCT1 and induces the expression of PD-L1 through NF-κB/COX-2 pathway, which reduces the cytotoxicity of T cells. (C) MCT-mediated lactate transport promotes tumor angiogenesis In oxidized tumor cells and endothelial cells, lactate is taken up via MCT1 and oxidized to pyruvate, and then inhibits PHD and catalyzes the hydroxylation of HIF-1α, which stimulates the transcription of vascular VEGF-a, VEGFR2 and bFGF. In addition, pyruvate can regulate the expression and activity of IκKβ, leading to phosphorylation and subsequent proteasome degradation of IκBα, nuclear translocation of NF-κB and transcription of the proangiogenic factor IL-8. VEGF-a, VEGFR2, bFGF and IL-8 are all pro-angiogenic factors with good characteristics.