title: PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53.
abstract: PRIMA-1 is a chemical compound identified as a growth suppressor of tumor cells expressing mutant p53. We previously found that in the MDA-MB-231 cell line expressing high level of the mutant p53-R280K protein, PRIMA-1 induced p53 ubiquitination and degradation associated to cell death. In this study, we investigated the ability of PRIMA-1 to induce autophagy in cancer cells. In MDA-MB-231 and HCT116 cells, expressing mutant or wild type p53, respectively, autophagy occurred following exposure to PRIMA-1, as shown by acridine orange staining, anti-LC3 immunofluorescence and immunoblots, as well as by electron microscopy. Autophagy was triggered also in the derivative cell lines knocked-down for p53, although to a different extent than in the parental cells expressing mutant or wild type p53. In particular, while wild type p53 limited PRIMA-1 induced autophagy, mutant p53 conversely promoted autophagy, thus sustaining cell viability following PRIMA-1 treatment. Therefore, the autophagic potential of PRIMA-1, besides being cell context dependent, could be modulated in a different way by the presence of wild type or mutant p53. Furthermore, since both cell lines lacking p53 were more sensitive to the cytotoxic effect of PRIMA-1 than the parental ones, our findings suggest that a deregulated autophagy may favor cell death induced by this drug.
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Russo
authors.forename: Laura
authors.initials: L
authors.lastname: Ottaggio
authors.forename: Giorgia
authors.initials: G
authors.lastname: Foggetti
authors.forename: Matilde
authors.initials: M
authors.lastname: Masini
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Masiello
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fronza
authors.forename: Paola
authors.initials: P
authors.lastname: Menichini
mesh_terms: D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000494:pharmacology*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53