Inhibition of nuclear factor kappaB induces apoptosis following treatment with tumor necrosis factor alpha and an antioxidant in human prostate cancer cells

• Published in: Cancer detection and prevention Vol. 26; no. 3; p. 229
• Main Authors: Gunawardena, Kushlani, Murray, Darrell K, Swope, Richard E, Meikle, A Wayne
• Format: Journal Article
• Language: English
• Published: England 2002
• Subjects: Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Computer Graphics; Humans; Male; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - drug effects; NF-kappa B - biosynthesis; NF-kappa B - drug effects; Proline - analogs & derivatives; Proline - therapeutic use; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Biosynthesis; Proteins - drug effects; Thiocarbamates - therapeutic use; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - therapeutic use
• ISSN: 0361-090X

Transforming growth factor beta-1 (TGFbeta-1) and tumor necrosis factor alpha (TNF-alpha), an activator of nuclear factor kappa B (NF-kappaB), modulate apoptosis and/or cell growth. This study was designed to investigate the activity of NF-kappaB and its regulation of inhibitor of apoptosis gene (c-IAP2) in two human prostate cancer cell lines, DU-145 (which is androgen unresponsive) and ALVA-101 (which is moderately androgen responsive). These cells were treated with and without various concentrations of a strong antioxidant, pyrrolidinedithiocarbamate (PDTC), and TNF-alpha at various time intervals. Following treatments, cell growth and apoptosis were determined by ELISA techniques. NF-kappaB activity was determined by electrophoretic mobility shift assay (EMSA), and c-IAP2 mRNA production was determined with Northern blot analysis. PDTC treatment significantly reduced cell growth up to 80% in both DU-145 and ALVA-101 cells. TNF-alpha and lower but not higher doses of PDTC combined demonstrated an additive inhibition of cell growth in both cell lines. Active NF-kappaB and c-IAP2 was blocked significantly following PDTC treatments, whereas treatments with TNF-alpha alone showed increased NF-kappaB activity and c-IAP2. However, when both PDTC and TNF-alpha were combined, nuclear presence of NF-kappaB and c-IAP2 were reduced significantly (P < 0.05) to levels observed with PDTC alone. In conclusion, the antioxidant, PDTC, appears to initiate apoptosis by blocking cytoplasmic NF-kappaB translocation to the nucleus where it normally activates the production of apoptosis-inhibitory proteins like c-IAP2. Both TNF-alpha and PDTC alone cause apoptosis and reduce cell growth, but their combined effects are additive in reducing cell growth of DU-145 and ALVA-101 human prostate cancer cells.