Blocking Lactate Export by Inhibiting the Myc Target MCT1 Disables Glycolysis and Glutathione Synthesis

Abstract

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1, and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, and reductions in glucose transport, and in levels of ATP, NADPH and glutathione. Reductions in glutathione then lead to increases in hydrogen peroxide, mitochondrial damage and, ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.

Cancer metabolism in space and time: Beyond the Warburg effect

“…The re mark able de pen dency for sur vival of hy poxic/ gly colytic can cer cells on the meta bolic pref er ences of nor moxic/ ox ida tive ones mo ti vated the de vel op ment of strate gies aimed to in ter fere with the ex change of lac tate. Ther a peu tic in ter ven tions could be aimed at in hibit ing MCT4 in hy poxic can cer cell com part ments [86], in hibit ing MCT1 [5,[87][88][89] and lac tate up take [90,91] in oxy genated/ ox ida tive can cer cells, in hibit ing LDHB [76,92] or, pos si bly, in hibit ing the mi to chon dr ial pyru vate car rier in ox ida tive can cer cells [93]. In our opin ion, fu ture ther a peu tic de vel op ments should aim at tar get ing the ox ida tive path way of lac tate in can cer cells that re side close to drug de liv er ing blood ves sels.…”

Genetic Disruption of Lactate/H+ Symporters (MCTs) and Their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin

“…Hypoxia via HIF1 controls intracellular pH (pHi) by inducing the membrane-bound carbonic anhydrases IX and XII (12)(13)(14) and a major H þ /lactate À symporter, MCT4 (15)(16)(17). Considering the key role of glycolysis in "glucoseaddicted" tumors, targeting this bioenergetic and anabolic pathway represents an attractive therapeutic approach (18)(19)(20)(21)(22). The regulation of pHi is a key determinant for many physiologic processes and is certainly essential in maintaining a high glycolytic rate.…”

“…BSG is a type I transmembrane glycoprotein that has been reported to be overexpressed in different metastatic tumor cells (24,26). Thus targeting BSG/ MCTs complex using a pharmacologic inhibitor or shRNA-mediated knockdown was reported to impair the in vitro and in vivo growth of pancreatic tumor cells (27), Ras-transformed fibroblasts, colon adenocarcinoma (21), and Myc-induced human malignancies (22), which suggested that blocking lactic acid export provides an efficient metabolic therapy to limit tumor cell growth (14).…”

Anticancer Effects of γ-Tocotrienol Are Associated with a Suppression in Aerobic Glycolysis

“…43) Lactate generated during glycolysis is excreted out of cells by monocarboxylate transporters and oncogenic c-Myc activity increases MCT-1 expression in several types of cancers. 44,45) In addition, treatments that inhibit c-Myc activity induce a reduction in MCT-1 expression and a subsequent reduction in cancer cell aerobic glycolysis and proliferation. 44,45) Results show that mammary cancer cells exposed to γ-tocotrienol treatment displayed a significant decrease in c-Myc, LDHA and MCT-1 levels and a corresponding reduction in lactate production.…”

“…44,45) In addition, treatments that inhibit c-Myc activity induce a reduction in MCT-1 expression and a subsequent reduction in cancer cell aerobic glycolysis and proliferation. 44,45) Results show that mammary cancer cells exposed to γ-tocotrienol treatment displayed a significant decrease in c-Myc, LDHA and MCT-1 levels and a corresponding reduction in lactate production. These findings strongly suggest that γ-tocotrienolinduced inhibition in c-Myc expression plays an important role in mediating γ-tocotrienol action in suppressing aerobic glycolysis and cancer cell proliferation.…”