Browsing by Author "Krebs, A. M."
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Item Open Access Polyol pathway links glucose metabolism to the aggressiveness of cancer cells(American Association for Cancer Research, 2018) Schwab, A.; Siddiqui, A.; Vazakidou, M. E.; Napoli, F.; Bottcher, M.; Menchicchi, B.; Raza, Umar; Saatçi, Özge; Krebs, 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, Özgür; Volante, M.; Greten, F. R.; Brabletz, T.; Ceppi, P.Cancer 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.