Molecular mechanisms of apoptosis
Our team focuses on two main themes : (1) the study of programmed cell deaths, with a special interest on the mechanisms of p53-dependent apoptosis; (2) the deciphering of the mechanisms of action of natural or synthetic molecules showing anti-cancer activities.
- The tumor suppressor p53 is the most frequently mutated gene in human cancer, with an overall mutation rate over 50%. In addition to its well-known role of transcription factor, we and other described that, in presence of an apoptotic stimulus, a fraction of p53 translocates to the mitochondria where it exerts to a pro-apoptotic activity. Mitochondrial p53 is able to interact with BAK, induce its oligomerization at the outer mitochondrial membrane and trigger the release of the mitochondrial effectors of apoptosis, such as cytochrome c, from the intermembrane space into the cytosol.
Our aim is to decipher this pathway of p53-mediated apoptosis. We are interested at determining what post-translocational modificatoin of p53 are required for or influential to its mitochondrial trafficking and pro-apoptotic activity at the mitochondria. We are also characterizing new interactions between p53 and mitochondrial proteins and analyzing their role in this pathway. Cancer cells are sensitive to this pathway that involves the mitochondrial translocation of p53. A better understanding of it will allow defining new therapeutic strategies to combat cancer, specifically aimed at triggering the mitochondrial translocation of p53.
- The head of the team, Prof. Patrick Dumont, previously participated to the development of anti-cancer molecules, including a novel amonafide derivative, less toxic and with a distinct mechanism of action, notably inducing autophagy and senescence in cancer cells. The molecule was evaluated in phase I clinical trial. He also investigated the mechanism of action of the Amarallidaceae isocarbostryl narciclasine. Recently, we studied in the lab the mechanisms underlying the cytotoxic activity of the natural polyphenol resveratrol (RSV) on colon cancer cells. We found that RSV induces DNA damage including double strand breaks by poisoning topoisomerase-2 alpha (Top2a), resulting in cell death by apoptosis. Current projects aim at characterizing at atomic resolution the Top2a-RSV interaction and develop novel RSV derivatives with a maximized Top2a poisoning activity.