Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells
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AbstractThe 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 implication in the application of proteasome-directed therapy for the treatment of cancer.
All Author(s) ListWu WKK, Cho CH, Lee CW, Wu YC, Yu L, Li ZJ, Wong CCM, Li HT, Zhang L, Ren SX, Che CT, Wu KC, Fan DM, Yu J, Sung JJY
Journal nameAutophagy
Detailed description(CHC as Co-correspondence author)
Volume Number6
Issue Number2
PublisherTaylor & Francis: STM, Behavioural Science and Public Health Titles
Pages228 - 238
LanguagesEnglish-United Kingdom
Keywordsautophagy; ERK; gastric cancer; proliferation; proteasome inhibitor
Web of Science Subject CategoriesCell Biology; CELL BIOLOGY

Last updated on 2020-25-10 at 01:17