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Induction of autophagy by proteasome inhibitor is associated with proliferative arrest in colon cancer cells.

Abstract
The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Blockade of UPS by proteasome inhibitors has been shown to activate autophagy. Recent evidence also suggests that proteasome inhibitors may inhibit cancer growth. In this study, the effect of a proteasome inhibitor MG-132 on the proliferation and autophagy of cultured colon cancer cells (HT-29) was elucidated. Results showed that MG-132 inhibited HT-29 cell proliferation and induced G(2)/M cell cycle arrest which was associated with the formation of LC3(+) autophagic vacuoles and the accumulation of acidic vesicular organelles. MG-132 also increased the protein expression of LC3-I and -II in a time-dependent manner. In this connection, 3-methyladenine, a Class III phosphoinositide 3-kinase inhibitor, significantly abolished the formation of LC3(+) autophagic vacuoles and the expression of LC3-II but not LC3-I induced by MG-132. Taken together, this study demonstrates that inhibition of proteasome in colon cancer cells lowers cell proliferation and activates autophagy. This discovery may shed a new light on the novel function of proteasome in the regulation of autophagy and proliferation in colon cancer cells.
AuthorsWilliam Ka Kei Wu, Ya Chun Wu, Le Yu, Zhi Jie Li, Joseph Jao Yiu Sung, Chi Hin Cho
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 374 Issue 2 Pg. 258-63 (Sep 19 2008) ISSN: 1090-2104 [Electronic] United States
PMID18638451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Microtubule-Associated Proteins
  • Proteasome Inhibitors
  • light chain 3, human
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • 3-methyladenine
  • Adenine
Topics
  • Adenine (analogs & derivatives, pharmacology)
  • Autophagy (drug effects)
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Colonic Neoplasms (pathology)
  • Cysteine Proteinase Inhibitors (pharmacology)
  • Cytoplasmic Vesicles (metabolism)
  • G2 Phase (drug effects)
  • Humans
  • Leupeptins (pharmacology)
  • Microtubule-Associated Proteins (biosynthesis)
  • Proteasome Inhibitors
  • Vacuoles (metabolism)

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