Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway

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-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increase...

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Published in:	Autophagy Vol. 16; no. 8; pp. 1436 - 1452
Main Authors:	Qureshi-Baig, Komal, Kuhn, Diana, Viry, Elodie, Pozdeev, Vitaly I., Schmitz, Martine, Rodriguez, Fabien, Ullmann, Pit, Koncina, Eric, Nurmik, Martin, Frasquilho, Sonia, Nazarov, Petr V., Zuegel, Nikolaus, Boulmont, Marc, Karapetyan, Yervand, Antunes, Laurent, Val, Daniel, Mittelbronn, Michel, Janji, Bassam, Haan, Serge, Letellier, Elisabeth
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 02-08-2020
Subjects:	Animals Autophagosomes - metabolism Autophagy Autophagy-Related Protein 5 - deficiency Autophagy-Related Protein 5 - metabolism cancer stem cell Carcinogenesis - pathology Cell Self Renewal Colon - pathology colorectal cancer Colorectal Neoplasms - etiology Colorectal Neoplasms - pathology Cytoskeletal Proteins - metabolism Disease Progression ezrin Humans hypoxia Hypoxia - complications Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Phenotype Phosphorylation protein kinase C Protein Kinase C - metabolism Research Paper self-renewal capacity Signal Transduction tumor-initiating cell hypoxia colorectal cancer cancer stem cell self-renewal capacity ezrin tumor-initiating cell Autophagy protein kinase C
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Summary:	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-enrichedpatient-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. ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CQ: chloroquine; CSC: cancer stem cells; CRC: colorectal cancer; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PRKC/PKC: protein kinase C; SQSTM1/p62: sequestosome 1; TICs: tumor-initiating cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	1554-8627 1554-8635
DOI:	10.1080/15548627.2019.1687213