Reactivation of mutant p53 by capsaicin, the major constituent of peppers

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.

Molecularly targeted therapies for p53-mutant cancers

“…To explore natural compounds that induce degradation of mutant p53, Garufi et al recently discovered that capsaicin, the constituent of peppers responsible for their pungency, could induce the protein degradation of mutant p53 (R175H, R273H) in both glioblastoma and breast cancer cell lines (67). Abrogation of mutant p53 by capsaicin treatment restored wild-type p53 activities, such as upregulation of PUMA and Bax, and induction of cancer cell death.…”

“…Abrogation of mutant p53 by capsaicin treatment restored wild-type p53 activities, such as upregulation of PUMA and Bax, and induction of cancer cell death. Interestingly, capsaicin also decreased the expression of MDR1 (multidrug resistance gene) and therefore sensitized tumors to chemotherapy drugs such as cisplatin (67). However, the mechanism by which capsaicin induces degradation of mutant p53 remains unknown.…”

Capsaicin reduces genotoxicity, colonic cell proliferation and preneoplastic lesions induced by 1,2-dimethylhydrazine in rats

“…Scientific reports on capsaicin potential carcinogenicity have yielded inconsistent findings (Bode and Dong 2011). Some studies have shown that capsaicin exerts anti-proliferative and pro-apoptotic effects on different cancer cell lines (Brown et al 2010;Díaz-Laviada 2010;Garufi et al 2016;Lau et al 2014) and might inhibit the metabolism of chemical carcinogens by interacting with a number of cytochrome P450 enzymes (CYPs) (Zhang et al 2012). On the other hand, Lee and Park have reported an association between capsaicin at high doses with mutagenicity and carcinogenicity (Lee and Park 2003).…”

Mechanistic study of nonivamide enhancement of hyperthermia-induced apoptosis in U937 cells

“…A TP53 (Tumor protein p53) gene mutation has been found in more than half of human cancers, suggesting that the TP53 gene plays a crucial role in suppressing tumor formation [16]. Capsaicin can reactivate mutant p53 in glioblastoma and lung cancer [17]; however, leukemic cells with mutant p53 are insensitive to capsaicin [18]. To resolve this incongruity, I have employed hyperthermia and nonivamide, which is a heat-stable analogue of capsaicin (http://www.hmdb.ca/metabolites/HMDB29846), to examine the anti-tumor effects of capsaicin analogues in U937 cells, which are a leukemic cell type with mutant p53 (46 base pair deletions, beginning at codon 132) [14].…”