Repression of protein translation and mTOR signaling by proteasome inhibitor in colon cancer cells.
Protein homeostasis relies on a balance between protein synthesis and protein degradation. The ubiquitin-proteasome system is a major catabolic pathway for protein degradation. In this respect, proteasome inhibition has been used therapeutically for the treatment of cancer. Whether inhibition of protein degradation by proteasome inhibitor can repress protein translation via a negative feedback mechanism, however, is unknown. In this study, proteasome inhibitor MG-132 lowered the proliferation of colon cancer cells HT-29 and SW1116. In this connection, MG-132 reduced the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and Ser2481 and the phosphorylation of its downstream targets 4E-BP1 and p70/p85 S6 kinases. Further analysis revealed that MG-132 inhibited protein translation as evidenced by the reductions of (35)S-methionine incorporation and polysomes/80S ratio. Knockdown of raptor, a structural component of mTOR complex 1, mimicked the anti-proliferative effect of MG-132. To conclude, we demonstrate that the inhibition of protein degradation by proteasome inhibitor represses mTOR signaling and protein translation in colon cancer cells.
Wu
William Ka Kei
WK
Institute of Digestive Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong. wukakei@cuhk.edu.hk
Volta
Viviana
V
Cho
Chi Hin
CH
Wu
Ya Chun
YC
Li
Hai Tao
HT
Yu
Le
L
Li
Zhi Jie
ZJ
Sung
Joseph Jao Yiu
JJ
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000201:enzymology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors; D011506:Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde