Pristimerin induces apoptosis by targeting the proteasome in prostate cancer cells.

Abstract

Pristimerin is a natural product derived from the Celastraceae and Hippocrateaceae families that were used as folk medicines for anti inflammation 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 C6 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 (IC50 2.2 micromol/L) and human prostate cancer 26S proteasome (IC50 3.0 micromol/L). The accumulation of ubiquitinated proteins and three proteasome target proteins, Bax, p27 and I kappa B-alpha, 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.

• Authors: Huanjie Yang, Kristin R Landis-Piwowar, Dayan Lu, Ping Yuan, Lihua Li, G Prem-Veer Reddy, Xiao Yuan, Q Ping Dou
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 103 Issue 1 Pg. 234-44 (Jan 01 2008) ISSN: 0730-2312 [Print] United States
• PMID: 17541980 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2007 Wiley-Liss, Inc.

Chemical References

• Androgens
• Cell Extracts
• Pentacyclic Triterpenes
• Protease Inhibitors
• Proteasome Inhibitors
• Protein Subunits
• Receptors, Androgen
• Triterpenes
• CTRL protein, human
• Serine Endopeptidases
• Proteasome Endopeptidase Complex
• celastrol

Topics

• Androgens (pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Extracts
• Cell Line, Tumor
• Computational Biology
• Electrons
• Humans
• Kinetics
• Male
• Models, Molecular
• Molecular Structure
• Pentacyclic Triterpenes
• Prostatic Neoplasms (enzymology, pathology)
• Protease Inhibitors (chemistry, pharmacology)
• Proteasome Endopeptidase Complex (chemistry, metabolism)
• Proteasome Inhibitors
• Protein Subunits (chemistry, metabolism)
• Rabbits
• Receptors, Androgen (metabolism)
• Serine Endopeptidases (metabolism)
• Triterpenes (chemistry, pharmacology)