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Pristimerin induces apoptosis by targeting the proteasome in prostate cancer cells
Author(s) -
Yang Huanjie,
LandisPiwowar Kristin R.,
Lu Dayan,
Yuan Ping,
Li Lihua,
Reddy G. PremVeer,
Yuan Xiao,
Dou Q. Ping
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21399
Subject(s) - proteasome , prostate cancer , lncap , cancer research , apoptosis , chemistry , cancer cell , cancer , androgen receptor , biology , biochemistry , medicine
Abstract Pristimerin is a natural product derived from the Celastraceae and Hippocrateaceae families that were used as folk medicines for antiinflammation in ancient times. Although it has been shown that pristimerin induces apoptosis in breast cancer cells, the involved mechanism of action is unknown. The purpose of the current study is to investigate the primary target of pristimerin in human cancer cells, using prostate cancer cells as a working model. Nucleophilic susceptibility and in silico docking studies show that C 6 of pristimerin is highly susceptible towards a nucleophilic attack by the hydroxyl group of N‐terminal threonine of the proteasomal chymotrypsin subunit. Consistently, pristimerin potently inhibits the chymotrypsin‐like activity of a purified rabbit 20S proteasome (IC 50 2.2 µmol/L) and human prostate cancer 26S proteasome (IC 50 3.0 µmol/L). The accumulation of ubiquitinated proteins and three proteasome target proteins, Bax, p27 and IκB‐α, in androgen receptor (AR)‐negative PC‐3 prostate cancer cells supports the conclusion that proteasome inhibition by pristimerin is physiologically functional. This observed proteasome inhibition subsequently led to the induction of apoptotic cell death in a dose‐ and kinetic‐dependent manner. Furthermore, in AR‐positive, androgen‐dependent LNCaP and AR‐positive, androgen‐independent C4‐2B prostate cancer cells, proteasome inhibition by pristimerin results in suppression of AR protein prior to apoptosis. Our data demonstrate, for the first time, that the proteasome is a primary target of pristimerin in prostate cancer cells and inhibition of the proteasomal chymotrypsin‐like activity by pristimerin is responsible for its cancer cell death‐inducing property. J. Cell. Biochem. 103: 234–244, 2008. © 2007 Wiley‐Liss, Inc.

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