The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells.

Abstract	Advanced prostate cancer is resistant to current therapeutic strategies. Bortezomib (Velcade; previously called PS-341) is a potent and specific inhibitor of the 26S proteasome that is currently in clinical trials for treatment of various malignancies, including prostate cancer. We investigated the effects of bortezomib on p53 in the LNCaP-Pro5 prostate cancer cell line. Bortezomib induced strong stabilization of p53, but it did not promote phosphorylation on serines 15 and 20, and p53 remained bound to its inhibitor, mdm2. Nonetheless, bortezomib stimulated p53 translocation to the nucleus (not mitochondria) and enhanced p53 DNA binding, accumulation of p53-dependent transcripts, and activation of a p53-responsive reporter gene. Furthermore, stable LNCaP-Pro5 transfectants of LNCaP-Pro5 expressing the p53 inhibitor human papillomavirus-E6 displayed reduced bortezomib-induced p53 activation and cell death. Together, our data demonstrate that bortezomib stimulates p53 activation via a novel mechanism.
Authors	Simon A Williams, David J McConkey
Journal	Cancer research (Cancer Res) Vol. 63 Issue 21 Pg. 7338-44 (Nov 01 2003) ISSN: 0008-5472 [Print] United States
PMID	14612532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References	Boronic Acids DNA, Neoplasm E6 protein, Human papillomavirus type 6 Nuclear Proteins Oncogene Proteins, Viral Proto-Oncogene Proteins Pyrazines Tumor Suppressor Protein p53 Bortezomib Etoposide MDM2 protein, human Proto-Oncogene Proteins c-mdm2 Peptide Hydrolases Proteasome Endopeptidase Complex ATP dependent 26S protease
Topics	Apoptosis (drug effects, physiology) Boronic Acids (pharmacology) Bortezomib Cell Line, Tumor DNA, Neoplasm (metabolism) Etoposide (pharmacology) Humans Male Nuclear Proteins Oncogene Proteins, Viral (genetics) Papillomaviridae (genetics) Peptide Hydrolases (metabolism) Phosphorylation (drug effects) Prostatic Neoplasms (drug therapy, genetics, metabolism) Proteasome Endopeptidase Complex Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-mdm2 Pyrazines (pharmacology) Subcellular Fractions (metabolism) Transcriptional Activation Transfection Tumor Suppressor Protein p53 (genetics, metabolism)

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