Glucose deprivation stimulates monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration
(2013) Oncogene : including Oncogene Reviews — Vol. 33, n° 31, p. 4060-4068 (2014)
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49DeSaedeleerOncogene2013.pdf
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49DeSaedeleerOncogene2013.pdf
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- Abstract
- The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose withdrawal dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this transcription-independent induction could be recapitulated using glycolysis inhibition, hypoxia, the mitochondrial uncoupler rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes formed preferentially in cell protrusions. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration was inhibited by providing an alternative oxidative fuel to glucose-starved cells or by targeting MCT1 using RNA interference or pharmacological inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer.
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De Saedeleer, C., Porporato, P., Copetti, T., Perez Escuredo, J., Payen, V., Brisson, L., Feron, O., & Sonveaux, P. (2013). Glucose deprivation stimulates monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Oncogene : including Oncogene Reviews, 33(31), 4060-4068. https://doi.org/10.1038/onc.2013.454 (Original work published 2014)