Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells.

Abstract

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 (<i>AKR1B1</i>) 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. <i>In vitro</i>, mesenchymal-like cancer cells showed increased AKR1B1 levels, and <i>AKR1B1</i> 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 TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ 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.<b>Significance:</b> A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. <i>Cancer Res; 78(7); 1604-18. ©2018 AACR</i>.