Propapoptotic effects of NF-kappaB in LNCaP prostate cancer cells lead to serine protease activation.
LNCaP prostate cancer cells are resistant to induction of apoptosis by gamma-irradiation and partially sensitive to TNF-alpha or FAS antibody, irradiation sensitizes cells to apoptosis induced by FAS antibody or TNF-alpha. LNCaP cell clones stably expressing IkappaBalpha super repressor were resistant to apoptosis induced by death ligands in the presence or absence of irradiation. IkappaBalpha super repressor expression also increased clonogenic survival after exposure to TNF-alpha+irradiation, but had no effect on survival after irradiation alone. IkappaBalpha super repressor expression blocked the increase of whole cell and cell surface FAS expression induced by TNF-alpha, but did not effect induction of FAS expression and cell surface FAS expression that resulted from irradiation. In cells expressing IkappaBalpha super repressor there was diminished activation of caspases-8 and -7 and diminished production of proscaspases-8 and -7, usually required for death induction in LNCaP cells. Peptide inhibitors of caspase activation complemented the IkappaBalpha super repressor inhibition of apoptosis, but peptide inhibitors of serine proteases had no effect on LNCaP cells expressing IkappaBalpha super repressor. Moreover, cleavage of a serine protease substrate was induced by treatment of LNCaP cells with TNF-alpha and irradiation. The data suggest that in LNCaP cells NF-kappaB mediates a proapoptotic pathway that leads to activation of proapoptotic serine proteases.
Department of Oncology, Lombardi Cancer Center, Georgetown University, 3800 Reservoir Rd, NW Washington, DC 20007-2197, USA.
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Kimura
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Gelmann
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy; D020169:Caspases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000072000:NF-KappaB Inhibitor alpha; D012697:Serine Endopeptidases; D020169:Caspases