title: Nutlin-3a, an MDM2 antagonist and p53 activator, helps to preserve the replicative potential of cancer cells treated with a genotoxic dose of resveratrol.
abstract: Resveratrol is a natural compound that has been intensely studied due to its role in cancer prevention and potential as an anti-cancer therapy. Its effects include induction of apoptosis and senescence-like growth inhibition. Here, we report that two cancer cell lines (U-2 OS and A549) differ significantly in their molecular responses to resveratrol. Specifically, in U-2 OS cells, the activation of the p53 pathway is attenuated when compared to the activation in A549 cells. This attenuation is accompanied by a point mutation (458: CGA→TGA) in the PPM1D gene and overexpression of the encoded protein, which is a negative regulator of p53. Experimentally induced knockdown of PPM1D in U-2 OS cells resulted in slightly increased activation of the p53 pathway, most clearly visible as stronger phosphorylation of p53 Ser37. When treated with nutlin-3a, a non-genotoxic activator of p53, U-2 OS and A549 cells both responded with substantial activation of the p53 pathway. Nutlin-3a improved the clonogenic survival of both cell lines treated with resveratrol. This improvement was associated with lower activation of DNA-damage signaling (phosphorylation of ATM, CHK2, and histone H2AX) and higher accumulation of cells in the G1 phase of the cell cycle. Thus, the hyperactivation of p53 by nutlin-3a helps to preserve the replicative potential of cells exposed to resveratrol.
authors.affiliation: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, ul. Wybrzeże Armii Krajowej 15, 44-101, Gliwice, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Zajkowicz
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Krześniak
authors.forename: Iwona
authors.initials: I
authors.lastname: Matuszczyk
authors.forename: Magdalena
authors.initials: M
authors.lastname: Głowala-Kosińska
authors.forename: Dorota
authors.initials: D
authors.lastname: Butkiewicz
authors.forename: Marek
authors.initials: M
authors.lastname: Rusin
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation / Q000235:genetics; D000071636:Protein Phosphatase 2C; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D017931:DNA Primers; D007093:Imidazoles; D010879:Piperazines; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D000077185:Resveratrol