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Proteasome inhibitor for cancer treatment

【摘要】:正The ubiquitin-proteasome degradation pathway plays an essential role in multiple cellular processes,including cell cycle progression,proliferation,apoptosis and angiogenesis.In vitro,in vivo and clinical studies suggest the potential use of proteasome inhibitors as novel anticancer drugs.In the current study,we are providing experimental evidence for that celastrol isolated from traditional Chinese medicine potently and preferentially inhibits the chymotrypsin-like activity of a purified 20S proteasome and human prostate cancer cellular 26S proteasome.Inhibition of the proteasome activity by celastrol in PC-3 (androgen receptor- or AR-negative) or LNCaP(AR-positive) cells results in the accumulation of ubiquitinated proteins and three natural proteasome substrates(I B-,Bax,and p27),accompanied by suppression of AR protein expression(in LNCaP cells) and induction of apoptosis.Treatments with celastrol resulted in tumor growth inhibition in prostate cancer xenografts,associated with suppression of the proteasomal activity and induction of apoptosis in vivo.Our results show that celastrol is a natural proteasome inhibitor that has a great potential for cancer treatment.By computational modeling,it was predicted that the ketone carbons of celastrol might interact with the catalytic site of chymotryptic subunit of the proteasome.Indeed,the reduced form of celastrol had significantly decreased proteasome inhibitory and apoptosis-inducing activities,suggesting that the ketone structure was an active site of celastrol.We further investigated the role of AR on cell death modulation in response to proteasome inhibition and found that proteasome inhibitor induced significantly higher caspase-3 activation in parental PC-3 cells compared to PC3-AR cells that stably overexpressed wild type AR.Co-treatment of proteasome inhibitor and the AR antagonist Casodex caused significant decrease in AR expression associated with an increase in caspase-3 activity in both LNCaP and PC3-AR cells.These results provide evidence for AR involvement in the regulation of proteasome inhibitor induced cell death.

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