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Mutant p53 melanoma cell lines respond differently to CP-31398-induced apoptosis Ho, Clement Kar-Ming

Abstract

p53, a tumour suppressor gene, is considered the guardian of genome which governs several important biological functions including cell cycle arrest, DNA repair and apoptosis. Under normal conditions, p53 is tightly regulated and constitutively expressed at a low level. In human cancers, p53 is one of the most frequently mutated genes with over 50% of all human malignancies containing an altered p53 gene. Many strategies have been developed in light of restoring wild-type p53 functions to altered p53. Recently, a small pharmacological compound, CP-31398, was found through random screening to have the ability to promote proper p53 protein folding, activate p53 transcription of downstream targets, and slow tumor growth in mice. Additionally, CP-31398 was found to be able to convert mutant p53 to wild-type conformation in several cell lines. In this study, we sought to examine if CP-31398 can revert all mutant p53 proteins to wild-type function. We studied a series of apoptotic responses to CP-31398 in three melanoma cell lines with various p53 mutation status. Upon a moderate dose of CP-31398 treatment (15 μg 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. Despite CP-31398 enhanced overall p53 protein level, its ability to promote proper folding of p53 protein was limited to CP-31398 sensitive MMRU and Me Wo cells. Although all cell lines showed an increased p21[Wafl] transcription, only sensitive cells showed an increased Bax and PUMA transcription, an altered mitochondrial membrane potential, followed by the release of cytochrome c, and cleaved caspases-9 and -3. We also demonstrated that Apaf-1, Fas and Fas-ligand were not involved in CP-31398 mediated apoptosis. In Summary, our results suggest that the ability of CP-31398 to revert mutant p53 proteins to wild-type conformation may be correlated to p53 mutation status. Mutant p53 reactivation by small molecules has an evident potential for the discovery of effective and specific anti-cancer drugs. To investigate p53 mutation-dependent in response to CP- 31398, further studies are required to explore the possibility of utilizing this compound as an anti-cancer therapeutic agent.

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