The role of MCT1 in tumor progression and targeted therapy: a comprehensive review

Abstract

Overexpression of monocarboxylate transporter 1 (MCT1) in tumor cells is often associated with poor prognosis. The established mechanisms through which MCT1 and its mediated lactate transport drive tumor progression are manifold. The classical mechanisms include fostering metabolic symbiosis among tumor cells, dampening the immune function of immune cells, and spurring tumor angiogenesis. Beyond these, new findings of MCT1's role in tumor progression have emerged. These new findings highlight MCT1's involvement in mediating the reverse Warburg effect, inhibiting ferroptosis, promoting protective autophagy, and augmenting tumor glycolysis. When acetate serves as a transport substrate for MCT1, additional mechanisms come into play. These encompass MCT1's participation in the acetylation of histone H3K27 and its role in upregulating c-Myc levels. Several studies have demonstrated that while selective MCT1 inhibitors can effectively impede tumor progression, they also face notable challenges. To address these, combining MCT1 inhibitors with other drugs appears to hold more promise.

Keywords: MCT1; MCT1 inhibitor; oncogenic mechanism; targeted therapy; tumor progression.

Figure 1

Classical mechanisms by which MCT1 promotes tumor progression. MCT1 promotes tumor progression through the promotion of metabolic symbiosis among tumor cells, the suppression of immune function in immune cells, and the promotion of tumor angiogenesis.

Figure 2

New findings on how MCT1 promotes tumor progression. New findings highlight MCT1’s involvement in mediating the reverse Warburg effect, inhibiting ferroptosis, promoting protective autophagy, and augmenting tumor glycolysis. When acetate serves as a transport substrate for MCT1, additional mechanisms come into play, including MCT1’s participation in the acetylation of histone H3K27 and its role in upregulating c-Myc levels.

Figure 3

Mechanism of action of selective MCT1 inhibitors. AZD3965, BAY-8002, 7ACC2, and AR-C155858 exert their inhibitory effects by binding to specific sites of MCT1. 3-BrPA acts by inducing methylation of the gene coding for MCT1. MicroRNAs act by inhibiting the associated mRNAs.