Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Cancer cells alter their metabolism to support their malignant properties. By transcriptomic analysis we identified the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) as strongly correlated with epithelial-to-mesenchymal transition (EMT). This association was confirmed staining 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 profiling confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGF-Beta signature genes. Mechanistically, excess glucose was found to promote EMT through autocrine TGF-Beta stimulation, while PP-deficient cells were refractory to glucose-induced EMT. PP represents a molecular link between glucose metabolism and cancer differentiation and aggressiveness, and a novel potential therapeutic target. Overall design: 3x3 biological replicated samples; 2 groups of samples with shRNA-mediated specific gene inhibition and scrambled control cells

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Schwab A, Siddiqui A, Vazakidou ME, Napoli F, Böttcher M, Menchicchi B, Raza U, Saatci Ö, Krebs AM, Ferrazzi F, Rapa I, Dettmer-Wilde K, Waldner MJ, Ekici AB, Rasheed SAK, Mougiakakos D, Oefner PJ, Sahin O, Volante M, Greten FR, Brabletz T, Ceppi P