PFT-alpha inhibits antibody-induced activation of p53 and pro-apoptotic signaling in 1-LN prostate cancer cells.
Antibodies against the COOH-terminal domain of cell surface GRP78 induce apoptosis in cancer cell lines via activation of p53 signaling. We now have studied the effects of PFT-alpha, an inhibitor of p53-mediated apoptotic pathways, on anti-GRP78 antibody-induced activation of p53 and pro-apoptotic signaling in 1-LN prostate cancer cells. Pretreatment of 1-LN cancer cells with this agent significantly inhibited antibody or doxorubicin-induced upregulation of p53. Concomitantly, PFT-alpha treatment prevented down regulation of ERK1/2 activation by either antibody or doxorubicin. Likewise, PFT-alpha prevented increases in the pro-apoptotic proteins BAD, BAK, BAX, PUMA, and NOXA as well as activation of caspases-3, -7, and -9. We conclude that antibody-induced apoptosis in prostate cancer cells is mediated predominantly by p53 using the mitochondrial pathway of apoptosis.
Misra
U K
UK
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Pizzo
S V
SV
D000912:Antibodies, Neoplasm / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D052160:Benzothiazoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000912:Antibodies, Neoplasm; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D052160:Benzothiazoles; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D020169:Caspases