Curcumin stabilizes p53 by interaction with NAD(P)H: quinone oxidoreductase 1 in tumor-derived cell lines

Abstract

Curcumin is a natural phytochemical with potent anti-neoplastic properties including modulation of p53.Targeting p53 activity has been suggested as an important strategy in cancer therapy. The purpose of this studywas to describe a mechanism by which curcumin restores p53 levels in human cancer cell lines.HeLa, SiHa, CaSki and MDA-MB-231 cells were exposed to curcumin and a pulse and chase and im-munoprecipitation assays were performed. Here we showed that curcumin increases the half-life of p53 by aphysical interaction between p53-NQO1 (p53 - NAD(P)H:quinone oxidoreductase 1) proteins after treatmentwith curcumin. Interestingly, the cell viability assay after treatment with curcumin showed that the cytotoxicactivity was selectively higher in cervical cancer cells contained wild type p53 but not in breast cancer cellscontained mutated p53. The cytotoxic effect of curcumin in cervical cancer cells was related to the complex p53-NQO1 that avoids the interaction between p53 and its negative regulator ubiquitin ligase E6-associated protein(E6AP). Finally, we demonstrated that in pancreatic epithelioid carcinoma cells (PANC1) that are knockout forNQO1, the reestablishment of NQO1 expression can stabilize p53 in presence of curcumin. Collectively, ourfindings showed that curcumin is necessary to promote the protein interaction of NQO1 with p53, therefore, itincreases the half-life of p53, and permits the cytotoxic effect of curcumin in cancer cells containing wild typep53. Ourfindings suggest that the use of curcumin may reactivate the p53 pathway in cancer cells with p53 wild-type.