Reference : Hypoxia-induced Autophagy Drives Colorectal Cancer Initiation and Progression by Acti...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/42813
Hypoxia-induced Autophagy Drives Colorectal Cancer Initiation and Progression by Activating the PRKC/PKC-EZR (Ezrin) Pathway
English
Qureshi-Baig, Komal [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Kuhn [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit > > Life Sciences Research Unit]
Viry, Elodie [Luxembourg Institute of Health > Laboratory of Experimental Cancer Research]
Pozdeev, Vitaly mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Schmitz, Martine mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Rodriguez, Fabien mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Ullmann, Pit [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Koncina, Eric mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Nurmik, Martin mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Frasquilho, Sonia [Integrated Biobank of Luxembourg]
Nazarov, Petr V [Luxembourg Institute of Health > Proteome and Genome Research Unit]
Zuegel, Nikolaus [Centre Hospitalier Emile Mayrisch > Department of Surgery]
Boulmont, Marc [Centre Hospitalier Emile Mayrisch > Department of Surgery]
Karapetyan, Yervand [Integrated Biobank of Luxembourg]
Antunes, Laurent [Laboratoire National de Santé > Department of Anatomic and Molecular Pathology]
Val, Daniel [Laboratoire National de Santé > Department of Anatomic and Molecular Pathology]
Mittelbronn, Michel mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Janji, Bassam [Luxembourg Institute of Health > Laboratory of Experimental Cancer Research]
Haan, Serge mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Letellier, Elisabeth mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
27-Nov-2019
Autophagy
Landes Bioscience
Yes (verified by ORBilu)
International
1554-8627
1554-8635
Georgetown
TX
[en] Autophagy ; cancer stem cell ; colorectal cancer ; ezrin ; hypoxia ; protein kinase C
[en] In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enriched patient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKCα as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients.
ELEVIE (28504270, R-AGR-3140), ondation Cancer (grant F1R-LSC-PAU-13HY2C), Fonds National de la Recherche (FNR) (under the AFR grant scheme and PRIDE scheme)
Researchers ; Professionals
http://hdl.handle.net/10993/42813
10.1080/15548627.2019.1687213

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