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Non-apoptotic cell death induced by opening the large conductance mechanosensitive channel MscL in hepatocellular carcinoma HepG2 cells.

Authors
  • Wen, Xiaoxu1
  • Tang, Siyang1
  • Hong, Feifan1
  • Wang, Xiaomin1
  • Chen, Sihan1
  • Hong, Lang1
  • Ye, Jia1
  • Li, Xia1
  • Shang, Shiqiang1
  • Jiang, Mizu1
  • Mao, Jianhua1
  • Shu, Qiang1
  • Li, Yuezhou2
  • 1 The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, NHC and CAMS Key Laboratory of Medical Neurobiology, Hangzhou, China. , (China)
  • 2 The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, NHC and CAMS Key Laboratory of Medical Neurobiology, Hangzhou, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Biomaterials
Publication Date
Aug 01, 2020
Volume
250
Pages
120061–120061
Identifiers
DOI: 10.1016/j.biomaterials.2020.120061
PMID: 32361391
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Most anticancer therapies trigger apoptosis to eliminate malignant cells. However, the majority of malignant cancer cells are resistant to apoptosis due to genetic mutations or heterogeneity. Here, we report that opening the pore of the bacterial large conductance mechanosensitivity channel (MscL) provides a novel approach of inducing non-apoptotic cell death. The gain-of-function mutant V23A-MscL and chemically responsive mutant G26C-MscL can be functionally expressed in hepatocellular carcinoma HepG2 cells. V23A-MscL spontaneously opens, and G26C-MscL also responds to its chemical activator MTSET. Opening of the MscL channel causes increased intracellular Ca2+ concentration and suppressed cell growth and viability. MTSET-activated G26C channels induce necrosis, while V23A-MscL expression leads to cytoplasmic vacuolization cell death in HepG2 cells and suppresses tumor growth in a mouse model. We propose that MscL may act as a nanovalve through which intracellular homeostasis suffers a disruption and results in malignant tumor cell damage, leading to a new strategy for cancer therapy. Copyright © 2020 Elsevier Ltd. All rights reserved.

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