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Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent

Authors
  • Shang, Chuquan1
  • Hassan, Bardes1, 2
  • Haque, Moinul1
  • Song, Yuqi1, 3
  • Li, Jing1, 4
  • Liu, Dongzhe1, 5, 6
  • Lipke, Eva1, 7
  • Chen, Will1
  • Giuriato, Sylvie
  • Lai, Raymond1, 8
  • 1 (W.C.)
  • 2 Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt
  • 3 Norman Bethune Health Science Center of Jilin University, Changchun 130021, China
  • 4 Electron Microscopy Center, Basic Medical Science College, Harbin Medical University, Harbin 150080, China
  • 5 Department of Hematology and Oncology, Shenzhen University General Hospital, Shenzhen 518055, China
  • 6 Laboratory of Biology and Chemistry, Basic Medical Science College, Harbin Medical University, Harbin 150080, China
  • 7 Department of Life Sciences, Albstadt-Sigmaringen University, 72488 Sigmaringen, Germany
  • 8 Department of Oncology, University of Alberta, Edmonton, AB T6G 2R3, Canada
Type
Published Article
Journal
Cancers
Publisher
MDPI AG
Publication Date
Jan 07, 2021
Volume
13
Issue
2
Identifiers
DOI: 10.3390/cancers13020181
PMID: 33430343
PMCID: PMC7825760
Source
PubMed Central
Keywords
License
Green

Abstract

Simple Summary Autophagy is a cell survival and recycling mechanism which protects cancer cells upon therapeutic drug treatment. Here we investigated the impact of autophagy inhibition in a cancer of lymphoid origin, namely ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We inhibited autophagy in two distinct cell subsets of ALK + ALCL, one of which we previously shown to possess more stem-like and tumorigenic properties. Our study found that blockage of autophagy in the stem-like subset resulted in marked drug-sensitization to crizotinib, a current therapeutic agent used to treat ALK + ALCL. We also found differential involvement of the Myc oncogene in the autophagy process within the two subsets and identified its relative importance to the stem-like population. Our research suggests inhibition of autophagy alongside crizotinib preferentially targets stem-like cells, thus improving crizotinib therapy. Abstract Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely R eporter U nresponsive ( RU ) and R eporter R esponsive ( RR ), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.

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