Induction of autophagy by proteasome inhibitor is associated with proliferative arrest in colon cancer cells.
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.
Wu
William Ka Kei
WK
Department of Pharmacology, Basic Medical Sciences Building, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. wukakei@cuhk.edu.hk
Wu
Ya Chun
YC
Yu
Le
L
Li
Zhi Jie
ZJ
Sung
Joseph Jao Yiu
JJ
Cho
Chi Hin
CH
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D061988:Proteasome Inhibitors; D014617:Vacuoles / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D061988:Proteasome Inhibitors; C025946:3-methyladenine; D000225:Adenine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde