The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis

SIMPLE SUMMARY: The characteristic metabolic hallmark of cancer cells is the massive catabolism of glucose by glycolysis, even under aerobic conditions—the so-called Warburg effect. Although energetically unfavorable, glycolysis provides “building blocks” to sustain the unlimited growth of malignant cells. Aberrant glycolysis is also responsible for lactate accumulation and acidosis in the tumor milieu, which fosters hypoxia and immunosuppression. One of the mechanisms used by cancer cells to increase glycolytic flow is the negative regulation of the proteins that conform the mitochondrial pyruvate carrier (MPC) complex, which transports pyruvate into the mitochondrial matrix to be metabolized in the tricarboxylic acid (TCA) cycle. Evidence suggests that MPC downregulation in tumor cells impacts many aspects of tumorigenesis, including cancer cell-intrinsic (proliferation, invasiveness, stemness, resistance to therapy) and -extrinsic (angiogenesis, anti-tumor immune activity) properties. In many cancers, but not in all, MPC downregulation is associated with poor survival. MPC regulation is therefore central to tackling glycolysis in tumors. ABSTRACT: Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. MPC activity has an important role in glucose homeostasis, and its alteration is associated with diabetes, heart failure, and neurodegeneration. In cancer, however, controversy surrounds MPC function. In some cancers, MPC upregulation appears to be associated with a poor prognosis. However, most transformed cells undergo a switch from oxidative to glycolytic metabolism, the so-called Warburg effect, which, amongst other possibilities, is induced by MPC malfunction or downregulation. Consequently, impaired MPC function might induce tumors with strong proliferative, migratory, and invasive capabilities. Moreover, glycolytic cancer cells secrete lactate, acidifying the microenvironment, which in turn induces angiogenesis, immunosuppression, and the expansion of stromal cell populations supporting tumor growth. This review examines the latest findings regarding the tumorigenic processes affected by MPC.