Abstract
The human prostatic carcinoma cell line LNCaP is sensitive to TNF-α treatment and expresses wild-type p53. To analyse the possible role of p53 in TNF-α-mediated apoptosis, we generated a derivative of LNCaP, LN-56, expressing a dominant-negative element of p53, GSE56. P53 inactivation in LN-56 was associated with an increased resistance to apoptosis induced by TNF-α. Surface expression of TNF-α receptors was unchanged in LN-56 compared to LNCaP. TNF-α treatment resulted in accumulation of p53 in LNCaP and upregulation of p21/WAF1. Activation of caspase-7 and PARP proteolysis were delayed in LN-56 under TNF-α treatment. TNF-α-induced apoptosis in LNCaP cells was accompanied by caspase-dependent proteolysis of p21/WAF1 and Rb, which was significantly attenuated in LN-56. Cytochrome c release was induced by TNF-α treatment in both cell lines, but caspase-9 was 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. Interestingly, accumulation of p53 in TNF-α-treated LNCaP cells was decreased 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 results indicate that p53 is involved in TNF-α-mediated apoptosis in LNCaP.
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Acknowledgements
We thank Dr Yuri Lazebnik (Cold Spring Harbor Lab., NY, USA) for the generous gift of antibodies to caspases-7. This work was supported by a V. A. Merit Award to MB Cohen, by NIH grant CA 76673 to MB Cohen, and by NIH grants CA 60730 and CA 75179 to AV Gudkov.
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Rokhlin, O., Gudkov, A., Kwek, S. et al. p53 is involved in tumor necrosis factor-α-induced apoptosis in the human prostatic carcinoma cell line LNCaP. Oncogene 19, 1959–1968 (2000). https://doi.org/10.1038/sj.onc.1203453
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DOI: https://doi.org/10.1038/sj.onc.1203453
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