Schwab, A.Siddiqui, A.Vazakidou, M. E.Napoli, F.Bottcher, M.Menchicchi, B.Raza, UmarSaatçi, ÖzgeKrebs, A. M.Ferrazzi, F.Rapa, I.Wilde, K. D.Waldner, M. J.Ekici, A. B.Rasheed, S. A. K.Mougiakakos, D.Oefner, P. J.Şahin, ÖzgürVolante, M.Greten, F. R.Brabletz, T.Ceppi, P.2019-02-212019-02-2120180008-5472http://hdl.handle.net/11693/50336Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFb signature genes. Excess glucose was found to promote EMT through autocrine TGFb stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.EnglishArticle10.1158/0008-5472.CAN-17-28341538-7445