Autophagy; cancer stem cell; colorectal cancer; ezrin; hypoxia; protein kinase C
Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
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 ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Schmitz, Martine ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Rodriguez, Fabien ; 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 ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Nurmik, Martin ; 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 ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Janji, Bassam; Luxembourg Institute of Health > Laboratory of Experimental Cancer Research
Haan, Serge ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Letellier, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Hypoxia-induced Autophagy Drives Colorectal Cancer Initiation and Progression by Activating the PRKC/PKC-EZR (Ezrin) Pathway
Publication date :
27 November 2019
Journal title :
Autophagy
ISSN :
1554-8635
Publisher :
Landes Bioscience, Georgetown, United States - Texas
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Funders :
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)