The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells.
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.
Williams
Simon A
SA
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
McConkey
David J
DJ
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008297:Male; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011719:Pyrazines / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D001897:Boronic Acids; D004273:DNA, Neoplasm; C118860:E6 protein, Human papillomavirus type 6; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease