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

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.
Authors	William Ka Kei Wu, Chi Hin Cho, Chung Wa Lee, Ya Chun Wu, Le Yu, Zhi Jie Li, Clover Ching Man Wong, Hai Tao Li, Lin Zhang, Shun Xiang Ren, Chun Tao Che, Kaichun Wu, Daiming Fan, Jun Yu, Joseph Jao Yiu Sung
Journal	Autophagy (Autophagy) Vol. 6 Issue 2 Pg. 228-38 (Feb 2010) ISSN: 1554-8635 [Electronic] United States
PMID	20087064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	CDKN1B protein, human Cyclin-Dependent Kinase Inhibitor p21 Cysteine Proteinase Inhibitors Intracellular Signaling Peptides and Proteins Leupeptins MAP1LC3A protein, human Microtubule-Associated Proteins Proteasome Inhibitors RNA, Small Interfering Cyclin-Dependent Kinase Inhibitor p27 MTOR protein, human Protein Serine-Threonine Kinases TOR Serine-Threonine Kinases Extracellular Signal-Regulated MAP Kinases Proteasome Endopeptidase Complex benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Topics	Animals Autophagy (physiology) Cell Cycle (drug effects) Cell Line, Tumor (drug effects) Cell Proliferation (drug effects) Cyclin-Dependent Kinase Inhibitor p21 (metabolism) Cyclin-Dependent Kinase Inhibitor p27 Cysteine Proteinase Inhibitors (pharmacology) Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism) Humans Intracellular Signaling Peptides and Proteins (metabolism) Leupeptins (pharmacology) Lysosomes (metabolism) Microtubule-Associated Proteins (metabolism) Phosphorylation Proteasome Endopeptidase Complex (metabolism) Proteasome Inhibitors Protein Serine-Threonine Kinases (metabolism) RNA, Small Interfering (genetics, metabolism) Signal Transduction (physiology) Stomach Neoplasms (pathology, physiopathology) TOR Serine-Threonine Kinases Vacuoles (drug effects, metabolism)

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