Cytokine-induced modulation of tumor suppressor gene expression in ovarian cancer cells: up-regulation of p53 gene expression and induction of apoptosis by tumor necrosis factor-alpha.

OBJECTIVE

Our purpose was to determine the effect of tumor necrosis factor-alpha on anti-oncogene expression and to investigate the relationship between the up-regulation of the p53 tumor suppressor gene and tumor necrosis factor-alpha-mediated apoptosis in epithelial ovarian cancer cell lines.

STUDY DESIGN

By means of Northern blot techniques p53 messenger ribonucleic acid expression was assayed in ovarian cancer cells. Tumor cells explanted from patients into Balb/c nude mice were exposed to supernatants from activated monocytes, activated T cells, or the recombinant cytokines interleukin-6 and tumor necrosis factor-alpha. Time- and dose-dependence of p53 up-regulation was measured. Induction of programmed cell death (apoptosis) by tumor necrosis factor-alpha was quantitated by means of a deoxyribonucleic acid fragmentation assay.

RESULTS

Detectable levels of messenger ribonucleic acid for p53 were seen in ovarian cancer cells. Tumor necrosis factor-alpha induced a significant up-regulation of p53 messenger ribonucleic acid levels in ovarian cancer cells grown in nude mice and in vitro, whereas interleukin-6 did not. The maximum level of induction was 8 hours, and the up-regulation of p53 was dose dependent. In addition, tumor necrosis factor-alpha induced a dose-dependent increase in deoxyribonucleic acid fragmentation.

CONCLUSION

Tumor necrosis factor-alpha induced up-regulation of p53 tumor suppressor gene expression in epithelial ovarian cancer cell lines, together with the induction of cell death by apoptosis.