Nutlin-3a, an MDM2 antagonist and p53 activator, helps to preserve the replicative potential of cancer cells treated with a genotoxic dose of resveratrol |
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Authors: | Artur Zajkowicz Ma?gorzata Krze?niak Iwona Matuszczyk Magdalena G?owala-Kosińska Dorota Butkiewicz Marek Rusin |
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Institution: | 1. Center for Translational Research and Molecular Biology of Cancer, Maria Sk?odowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, ul. Wybrze?e Armii Krajowej 15, 44-101, Gliwice, Poland 2. Department of Bone Marrow Transplantation, Maria Sk?odowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101, Gliwice, Poland
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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. |
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