p53 is involved in tumor necrosis factor-alpha-induced apoptosis in the human prostatic carcinoma cell line LNCaP

The human prostatic carcinoma cell line LNCaP is sensitive to TNF-alpha tre atment and expresses wild-type p53, To analyse the possible role of p53 in TNF-alpha-mediated apoptosis, we generated a derivative of LNCaP, LN-56, ex pressing a dominant-negative element of p53, GSE56, P53 inactivation in LN- 56 was associated with an increased resistance to apoptosis induced by TNF- alpha, Surface expression of TNF-alpha receptors was unchanged in LN-56 com pared to LNCaP, TNF-alpha treatment resulted in accumulation of p53 in LNCa P and upregulation of p21/WAF1, Activation of caspase-7 and PARP proteolysi s were delayed in LN-56 under TNF-alpha treatment. TNF-alpha-induced apopto sis in LNCaP cells was accompanied by caspase-dependent proteolysis of p21/ WAF1 and Rb, which was significantly attenuated in LN-56, Cytochrome c rele ase was induced by TNF-alpha treatment in both cell lines, but caspase-9 wa s not activated. LNCaP and LN-56 were injected s.c. in nude mice and tumors were identified in all LN-56, but not LNCaP, bearing mice indicating that p53 plays an important role in growth control of prostatic neoplasms, Inter estingly, accumulation of p53 in TNF-alpha-treated LNCaP cells was decrease d in the presence of the caspase inhibitor Z-VAD-FMK, suggesting a new role of activated caspases in acceleration of p53 response, In summary, these r esults indicate that p53 is involved in TNF-alpha-mediated apoptosis in LNC aP.