title: Gambogic acid counteracts mutant p53 stability by inducing autophagy.
abstract: Mutant p53 (mutp53) proteins are frequently present at higher levels than the wild-type (wt) protein in tumors, and some of them can acquire oncogenic properties. Consistently, knockdown of mutp53 protein in human cancer cell lines leads to reduced cell proliferation and invasion as well as to an increased sensitivity to some anticancer drugs. Therefore, the exploitation of cellular pathways and/or molecules that promote mutp53 degradation may have a therapeutic interest. Recently, autophagy is emerging as an important pathway involved in the stability of mutp53. In this paper, we explored the autophagic potential of gambogic acid (GA), a molecule that stimulates the degradation of mutp53 and increases the sensitivity of cancer cells to chemotherapeutic agents. We demonstrated that GA may induce mutp53 degradation through autophagy in cancer cells expressing the p53-R280K (MDA-MB-231) and the p53-S241F (DLD1) proteins. The inhibition of autophagy with bafilomycin A1 or chloroquine counteracted mutp53 degradation by GA. However, the autophagy induction and mutp53 degradation affected cell survival and proliferation only at low GA concentrations. At higher GA concentrations, when cells undergo massive apoptosis, autophagy is no longer detectable by immuno-fluorescence analysis. We concluded that autophagy is a relevant pathway for mutp53 degradation in cancer cells but it contributes only partially to GA-induced cell death, in a time and dose-dependent manner.
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Foggetti
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ottaggio
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Russo
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Monti
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Degan
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fronza
authors.affiliation: U.O.C. Mutagenesi, IRCCS AOU San Martino-IST, 16132 Genova, Italy. Electronic address: paola.menichini@hsanmartino.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Menichini
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D009154:Mutation; D055550:Protein Stability / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D016159:Tumor Suppressor Protein p53; D044004:Xanthones; C052659:gambogic acid
keywords: Apoptosis; Autophagy; Gambogic acid; Mutant p53