Schwab, Annemarie and Siddiqui, Aarif and Vazakidou, Maria Eleni and Napoli, Francesca and Boettcher, Martin and Menchicchi, Bianca and Raza, Umar and Saatci, Ozge and Krebs, Angela M. and Ferrazzi, Fulvia and Rapa, Ida and Dettmer-Wilde, Katja and Waldner, Maximilian J. and Ekici, Arif B. and Rasheed, Suhail Ahmed Kabeer and Mougiakakos, Dimitrios and Oefner, Peter J. and Sahin, Ozgur and Volante, Marco and Greten, Florian R. and Brabletz, Thomas and Ceppi, Paolo (2018) Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells. CANCER RESEARCH, 78 (7). pp. 1604-1618. ISSN 0008-5472, 1538-7445
Full text not available from this repository. (Request a copy)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 (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 TGF beta signature genes. Excess glucose was found to promote EMT through autocrine TGF beta 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. Significance: A glucose-transforming pathway in TGF beta-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. (C) 2018 AACR.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TO-MESENCHYMAL TRANSITION; STEM-CELLS; E-CADHERIN; HEPATOCELLULAR-CARCINOMA; INDUCED EMT; METASTASIS; EXPRESSION; ZEB1; MODULATION; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2020 07:32 |
| Last Modified: | 20 Mar 2020 07:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14759 |
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