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Hypoxia-induced Autophagy Drives Colorectal Cancer Initiation and Progression by Activating the PRKC/PKC-EZR (Ezrin) Pathway
- Source :
- Autophagy, article-version (VoR) Version of Record
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Carcinogenesis
Colorectal cancer
Mice, SCID
Biochemistry, biophysics & molecular biology [F05] [Life sciences]
Autophagy-Related Protein 5
tumor-initiating cell
Ezrin
Mice, Inbred NOD
Cell Self Renewal
Phosphorylation
Hypoxia
Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]
Protein Kinase C
Tumor initiating cell
Phenotype
Disease Progression
Neoplastic Stem Cells
medicine.symptom
Colorectal Neoplasms
Signal Transduction
Research Article
Research Paper
congenital, hereditary, and neonatal diseases and abnormalities
cancer stem cell
Colon
colorectal cancer
self-renewal capacity
Biology
03 medical and health sciences
Cancer stem cell
mental disorders
medicine
Autophagy
Animals
Humans
Molecular Biology
Protein kinase C
030102 biochemistry & molecular biology
hypoxia
Autophagosomes
Cell Biology
Hypoxia (medical)
medicine.disease
nervous system diseases
ezrin
body regions
Cytoskeletal Proteins
030104 developmental biology
Cancer research
human activities
protein kinase C
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Autophagy, article-version (VoR) Version of Record
- Accession number :
- edsair.doi.dedup.....9b3eeb59245ff91b1693eba9d80acb46