Abstract
BackgroundMutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms.Methodsp53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53.ResultsHere, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins.ConclusionThese findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death.
Highlights
Mutations in the p53 oncosuppressor gene are highly frequent in human cancers
We have previously shown that autophagy is involved in mutp53 degradation, with the consequence of changing the balance between folded–misfolded p53 proteins and restore wild-type over mutant p53 functions [17, 18]
We found that CPS-induced cell death in mutant p53-carrying cells was, at least in part, dependent on p53 reactivation, as evidenced by experiments using Small interference RNA (siRNA) interference for p53
Summary
Mutations in the p53 oncosuppressor gene are highly frequent in human cancers These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. 55 % of human tumors have loss of wild-type (wt) p53 function mainly due to point mutations in the DNA-binding domain (DBD) ([3, 4], http://p53.iarc.fr), which partially or completely distort p53 protein conformation [5]. These findings indicate that the presence of a functional wtp is incompatible with neoplastic cell growth [6]. The search of novel mutp53-targeting molecules is an emergent field of research due to the important implications in cancer therapy
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