C K Ho1, G Li. 1. Department of Medicine, Division of Dermatology, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
Abstract
BACKGROUND: p53, a commonly mutated gene in human cancers, participates in cell cycle arrest, DNA repair and apoptosis. A small pharmacological compound, CP-31398, was found to have the ability to promote proper p53 protein folding, activate p53 transcription of downstream targets, and slow tumour growth in mice. Additionally, CP-31398 was found to be able to convert mutant p53 to wild-type conformation in several cell lines. OBJECTIVES: To examine if CP-31398 can revert all mutant p53 proteins to wild-type function. METHODS: We studied a series of apoptotic responses to CP-31398 in three melanoma cell lines varying in p53 mutation status. RESULTS: Upon a moderate dose of CP-31398 treatment (15 microg mL(-1)), only the wild-type p53 MMRU and the single p53 point mutation MeWo cells exhibited apoptosis. Another melanoma cell line, Sk-mel-110, containing multiple p53 mutations, did not exhibit apoptosis. Although CP-31398 enhanced overall p53 protein level, its ability to promote proper folding of p53 protein was limited to CP-31398-sensitive MMRU and MeWo cells. These sensitive cells showed an increased Bax and PUMA transcription, altered mitochondrial membrane potential, followed by the release of cytochrome c, and cleaved caspase-9 and caspase-3. We also demonstrated that Apaf-1 was not involved in CP-31398-mediated apoptosis. CONCLUSIONS: Our results suggest that the ability of CP-31398 to revert mutant p53 proteins to wild-type conformation may be correlated to p53 mutational status. More studies are necessary, to further investigate the effect of CP-31398 on mutant p53 and its potential applications as an anticancer agent.
BACKGROUND:p53, a commonly mutated gene in humancancers, participates in cell cycle arrest, DNA repair and apoptosis. A small pharmacological compound, CP-31398, was found to have the ability to promote proper p53 protein folding, activate p53 transcription of downstream targets, and slow tumour growth in mice. Additionally, CP-31398 was found to be able to convert mutant p53 to wild-type conformation in several cell lines. OBJECTIVES: To examine if CP-31398 can revert all mutant p53 proteins to wild-type function. METHODS: We studied a series of apoptotic responses to CP-31398 in three melanoma cell lines varying in p53 mutation status. RESULTS: Upon a moderate dose of CP-31398 treatment (15 microg mL(-1)), only the wild-type p53 MMRU and the single p53 point mutation MeWo cells exhibited apoptosis. Another melanoma cell line, Sk-mel-110, containing multiple p53 mutations, did not exhibit apoptosis. Although CP-31398 enhanced overall p53 protein level, its ability to promote proper folding of p53 protein was limited to CP-31398-sensitive MMRU and MeWo cells. These sensitive cells showed an increased Bax and PUMA transcription, altered mitochondrial membrane potential, followed by the release of cytochrome c, and cleaved caspase-9 and caspase-3. We also demonstrated that Apaf-1 was not involved in CP-31398-mediated apoptosis. CONCLUSIONS: Our results suggest that the ability of CP-31398 to revert mutant p53 proteins to wild-type conformation may be correlated to p53 mutational status. More studies are necessary, to further investigate the effect of CP-31398 on mutant p53 and its potential applications as an anticancer agent.