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

Komal Qureshi-Baig, Diana Kuhn, Elodie Viry, Vitaly I. Pozdeev, Martine Schmitz, Fabien Rodriguez, Pit Ullmann, Eric Koncina, Martin Nurmik, Sonia Frasquilho, Petr V. Nazarov, Nikolaus Zuegel, Marc Boulmont, Yervand Karapetyan, Laurent Antunes, Daniel Val, Michel Mittelbronn, Bassam Janji, Serge Haan, Elisabeth Letellier*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)

Abstract

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. Abbreviations: 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.

Original languageEnglish
Pages (from-to)1436-1452
Number of pages17
JournalAutophagy
Volume16
Issue number8
DOIs
Publication statusPublished - 2 Aug 2020

Keywords

  • Autophagy
  • cancer stem cell
  • colorectal cancer
  • ezrin
  • hypoxia
  • protein kinase C
  • self-renewal capacity
  • tumor-initiating cell

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