Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells
| العنوان: | Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells |
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| المؤلفون: | Dimitrios Mougiakakos, Katja Dettmer-Wilde, Thomas Brabletz, Peter J. Oefner, Arif B. Ekici, Annemarie Schwab, Maria Eleni Vazakidou, Fulvia Ferrazzi, Florian R. Greten, Aarif Siddiqui, Ozge Saatci, Angela M. Krebs, Ida Rapa, Martin Böttcher, Paolo Ceppi, Ozgur Sahin, Bianca Menchicchi, Marco Volante, Maximilian J. Waldner, Umar Raza, Suhail Ahmed Kabeer Rasheed, Francesca Napoli |
| المساهمون: | Raza, Umar, Saatçi, Özge, Şahin, Özgür |
| المصدر: | Cancer Research |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, L-Iditol 2-Dehydrogenase, Cancer Research, Epithelial-Mesenchymal Transition, Lung Neoplasms, Mice, 03 medical and health sciences, HT29 Cells, Polyol pathway, Aldehyde Reductase, Transforming Growth Factor beta, Cell Line, Tumor, medicine, Animals, Humans, RNA, Small Interfering, Autocrine signalling, A549 cell, Gene knockdown, Chemistry, HEK 293 cells, Cancer, HCT116 Cells, medicine.disease, Glucose, HEK293 Cells, 030104 developmental biology, Oncology, A549 Cells, Colonic Neoplasms, embryonic structures, Cancer cell, MCF-7 Cells, Cancer research, RNA Interference |
| الوصف: | 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. This work was supported by the Interdisciplinary Center for Clinical Research (IZKF) of the University of Erlangen-Nuremberg, the Deutsche Krebshilfe grant number 70112536, the IALSC Lung Cancer Young Investigator Award (to P. Ceppi), and by the Clinical Research GroupKFO262 funded by the German Research Foundation. This work was partially presented at the American Association for Cancer Research 2017 annual meeting. Special thanks to Dr. H. Wurdak (University of Leeds) for critical discussion. |
| وصف الملف: | application/pdf |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f3d28e16546b91ef4bc654713c429901 https://doi.org/10.1158/0008-5472.can-17-2834 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f3d28e16546b91ef4bc654713c429901 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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