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oai:repisalud.isciii.es:20.500.12105/202172024-11-29T06:00:43Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967
Repisalud author Brandi, Jessica author Cecconi, Daniela author Cordani, Marco author Torrens-Mas, Margalida author Pacchiana, Raffaella author Dalla Pozza, Elisa author Butera, Giovanna author Manfredi, Marcello author Marengo, Emilio author Oliver, Jordi author Roca, Pilar author Dando, Ilaria author Donadelli, Massimo 2024-07-09T09:12:50Z 2024-07-09T09:12:50Z 2016-12 Brandi J, Cecconi D, Cordani M, Torrens-Mas M, Pacchiana R, Dalla Pozza E, et al. The antioxidant uncoupling protein 2 stimulates hnRNPA2/B1, GLUT1 and PKM2 expression and sensitizes pancreas cancer cells to glycolysis inhibition. Free Radic Biol Med. 2016 Dec;101:305-16. 10.1016/j.freeradbiomed.2016.10.499 1873-4596 Free radical biology & medicine https://hdl.handle.net/20.500.13003/20197 27989750 L612983104 2-s2.0-84994752044 http://hdl.handle.net/20.500.12105/20217 390701300027 Several evidence indicate that metabolic alterations play a pivotal role in cancer development. Here, we report that the mitochondrial uncoupling protein 2 (UCP2) sustains the metabolic shift from mitochondrial oxidative phosphorylation (mtOXPHOS) to glycolysis in pancreas cancer cells. Indeed, we show that UCP2 sensitizes pancreas cancer cells to the treatment with the glycolytic inhibitor 2-deoxy-D-glucose. Through a bidimensional electrophoresis analysis, we identify 19 protein species differentially expressed after treatment with the UCP2 inhibitor genipin and, by bioinformatic analyses, we show that these proteins are mainly involved in metabolic processes. In particular, we demonstrate that the antioxidant UCP2 induces the expression of hnRNPA2/B1, which is involved in the regulation of both GLUT1 and PKM2 mRNAs, and of lactate dehydrogenase (LDH) increasing the secretion of L-lactic acid. We further demonstrate that the radical scavenger N-acetyl-L-cysteine reverts hnRNPA2/B1 and PKM2 inhibition by genipin indicating a role for reactive oxygen species in the metabolic reprogramming of cancer cells mediated by UCP2. We also observe an UCP2-dependent decrease in mtOXPHOS complex I (NADH dehydrogenase), complex IV (cytochrome c oxidase), complex V (ATPase) and in mitochondrial oxygen consumption, suggesting a role for UCP2 in the counteraction of pancreatic cancer cellular respiration. All these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation with the concomitant metabolic shift from mtOXPHOS to the glycolytic pathway. eng The antioxidant uncoupling protein 2 stimulates hnRNPA2/B1, GLUT1 and PKM2 expression and sensitizes pancreas cancer cells to glycolysis inhibition research article