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Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells.

Authors
  • Wu, William Ka Kei
  • Cho, Chi Hin
  • Lee, Chung Wa
  • Wu, Ya Chun
  • Yu, Le
  • Li, Zhi Jie
  • Wong, Clover Ching Man
  • Li, Hai Tao
  • Zhang, Lin
  • Ren, Shun Xiang
  • Che, Chun Tao
  • Wu, Kaichun
  • Fan, Daiming
  • Yu, Jun
  • Sung, Joseph Jao Yiu
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Feb 01, 2010
Volume
6
Issue
2
Pages
228–238
Identifiers
PMID: 20087064
Source
Medline
License
Unknown

Abstract

The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.

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