title: 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.affiliation: Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, P.R. China. wukakei@cuhk.edu.hk
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
authors.forename: Chung Wa
authors.initials: CW
authors.lastname: Lee
authors.forename: Ya Chun
authors.initials: YC
authors.lastname: Wu
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.forename: Zhi Jie
authors.initials: ZJ
authors.lastname: Li
authors.forename: Clover Ching Man
authors.initials: CC
authors.lastname: Wong
authors.forename: Hai Tao
authors.initials: HT
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Shun Xiang
authors.initials: SX
authors.lastname: Ren
authors.forename: Chun Tao
authors.initials: CT
authors.lastname: Che
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph Jao Yiu
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000473:pathology / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde