Activation of PP2A modulates the DNA damage response
Saverio Minucci, full professor of General and Clinical Pathology at the Department of Oncology and Hemato-Oncology of the University of Milan and Principal Investigator at the Department of Experimental Oncology of the IEO (European Institute of Oncology), will hold a seminar at CEINGE entitled "Activation of PP2A modulates the DNA damage response" (start at 12.00)
Professor Minucci is the author of more than 180 publications in international scientific journals and is a prominent figure in the field of Molecular Oncology. He studies chromatin alterations in tumorigenesis. During his post-specialization studies in the United States (NIH), he made important contributions to the understanding of the molecular mechanisms of operation of retinoic acid receptors (for which he received the FARE award), and was a pioneer in study of the interaction of these factors with chromatin. Upon his return to Italy, he made fundamental contributions to the identification of various chromatin alterations in tumourigenesis and to the identification of new molecular targets (such as histone deacetylases) in tumor therapy.
Host researcher: Massimo Zollo
What talking about
We have previously shown that PP2A integrates metabolic sensing with the the DNA-Damage Response (DDR) in yeast. Through a pharmacological and genetic approach, we found that interfering with mitochondrial oxidative phosphorylation and reducing glucose availability leads to activation of PP2A. Indeed, the combination of metformin (the most commonly used drug for type 2 diabetes, which inhibits mitochondrial complex I) with glucose starvation increased PP2A activity. In Triple Negative Breast Cancer (TNBC) cell lines and patient-derived tumors, metformin and glucose starvation enhanced the efficacy of low-dose, DNA-damaging chemotherapy. We demonstrated that activation of PP2A by metformin and glucose starvation attenuated the DDR triggered by chemotherapy, thus preventing the cell cycle arrest necessary for DNA repair and increasing genomic fragmentation, which finally led to cell death. In mouse models of TNBC, metformin and cycles of intermittent fasting (which lowered blood glucose) increased the efficacy of low-dose chemotherapy and induced tumor regression. Targeting the DDR is considered an attractive therapeutic opportunity, based on the intrinsic genomic instability of tumor cells. Here we provide a metabolic strategy to mitigate the DDR at multiple levels, which is safe, tolerable and of potential clinical use.