Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Schwab A, Siddiqui A, Vazakidou ME, Napoli F, Böttcher M, Menchicchi B, Raza U, Saatci O, Krebs A, Ferrazzi F, Rapa I, Dettmer-Wilde K, Waldner M, Ekici AB, Rasheed SAK, Mougiakakos D, Oefner PJ, Sahin O, Volante M, Greten FR, Brabletz T, Ceppi P (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Cancer Research American Association for Cancer Research

DOI: 10.1158/0008-5472.CAN-17-2834

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-? signature genes. Excess glucose was found to promote EMT through autocrine TGF-? 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.

Authors with CRIS profile

Annemarie Schwab Interdisziplinäres Zentrum für Klinische Forschung IZKF Nachwuchsgruppe 1 Prof. Dr. Ceppi Mohammad Siddiqui Interdisziplinäres Zentrum für Klinische Forschung IZKF Nachwuchsgruppe 1 Prof. Dr. Ceppi Maria Eleni Vazakidou Interdisziplinäres Zentrum für Klinische Forschung IZKF Nachwuchsgruppe 1 Prof. Dr. Ceppi Martin Böttcher Department of Medicine 5 – Haematology and Oncology Bianca Menchicchi Erlangen Graduate School in Advanced Optical Technologies (SAOT) Angela Krebs Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Fulvia Ferrazzi Institute of Human Genetics Maximilian Waldner Professur für Funktionelle Bildgebung in der Medizin Arif Bülent Ekici Institute of Human Genetics Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Paolo Ceppi Interdisziplinäres Zentrum für Klinische Forschung IZKF Nachwuchsgruppe 1 Prof. Dr. Ceppi

Involved external institutions

Universität Regensburg DE Germany (DE) Bilkent University / Bilkent Üniversitesi TR Turkey (TR) University of Turin / Università degli Studi di Torino (UNITO) IT Italy (IT) Institut für Tumorbiologie und experimentelle Therapie / Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus DE Germany (DE) National University of Singapore (NUS) SG Singapore (SG)

How to cite

APA:

Schwab, A., Siddiqui, A., Vazakidou, M.E., Napoli, F., Böttcher, M., Menchicchi, B.,... Ceppi, P. (2018). Polyol pathway links glucose metabolism to the aggressiveness of cancer cells. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-17-2834

MLA:

Schwab, Annemarie, et al. "Polyol pathway links glucose metabolism to the aggressiveness of cancer cells." Cancer Research (2018).

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