Genetic Disruption of Lactate/H+ Symporters (MCTs) and their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes suggérant l'intérêt d'une stratégie thérapeutique basée sur l'inhibition de MCT1 et MCT4, seule ou en combinaison avec la phenformine, pour le traitement de tumeurs dont le métabolisme est fortement glycolytique
Rapidly growing glycolytic tumors require energy and intracellular pH (pHi) homeostasis through the activity of two major MonoCarboxylate Transporters, MCT1 and the hypoxia-inducible MCT4, in intimate association with the glycoprotein CD147/BASIGIN (BSG). To further explore and validate the blockade of lactic acid export as an anticancer strategy, we disrupted, via Zinc Finger Nucleases, MCT4 and BASIGIN genes in colon adenocarcinoma (LS174T) and glioblastoma (U87) human cell lines. First, we showed that homozygous loss of MCT4 dramatically sensitized cells to the MCT1 inhibitor AZD3965. Second, we demonstrated that knockout of BSG lead to a decrease in lactate transport activity of MCT1 and MCT4 by 10- and 6-fold, respectively. Consequently, cells accumulated an intracellular pool of lactic and pyruvic acids, magnified by the MCT1 inhibitor decreasing further pHi and glycolysis. As a result, we found that these glycolytic/MCT-deficient cells resumed growth by redirecting their metabolism towards OXPHOS. Thirdly, we showed that in contrast to parental cells, BSG-null cells became highly sensitive to phenformin, an inhibitor of mitochondrial complex I. Phenformin addition to these MCT-disrupted cells in normoxic and hypoxic conditions induced a rapid drop in cellular ATP inducing cell death by 'metabolic catastrophe'. Finally, xenograft analysis confirmed the deleterious tumor growth effect of MCT1/MCT4 ablation, an action enhanced by phenformin treatment. Collectively, these findings highlight that inhibition of the MCT/BSG complexes alone or in combination with phenformin provides an acute anticancer strategy to target highly glycolytic tumors. This genetic approach validates the anticancer potential of the MCT1 and MCT4 inhibitors in current development.
Cancer Research 2014