Caspase 9 is required for p53-dependent apoptosis and chemosensitivity in a human ovarian cancer cell line

Abstract

The p53 gene suppresses tumor cell growth by inducing cell cycle arrest or apoptosis. Loss of its apoptosis activity has been implicated not only in tumor development but also in chemoresistance. We previously reported that targeting p53 for degradation by the human HPV E6 gene in the ovarian cancer cell line PA1 leads to an increase in the chemoresistant phenotype. Here we investigate the relationship between loss of p53-dependent caspase activation and chemosensitivity. In PA1-neo cells with wild-type p53, the activation of caspases including caspases 9, 8, 7 and 3 and cleavage of PARP were detected following adriamycin or etoposide treatment, whereas no such changes were observed in PA1-E6 cells whose p53 is degraded, suggesting that loss of p53 impairs caspase activation. Importantly, we showed that loss of caspase activation in PA1-E6 cells correlates with increased cell survival. Moreover, PA1 cells overexpressing a dominant negative caspase 9 were found to have decreased caspase-dependent apoptosis, as compared with vector control cells. Furthermore, these dominant negative caspase 9 expressing cells were resistant to chemotherapeutic agent-induced killing. Our results suggest that caspase 9 may be an important target for anticancer drug development. Thus, identifying novel compounds that can activate caspase 9 may be a strategy for overcoming a defect in the p53 apoptosis pathway.