Programmed cell death in biology and medicine
Boris Zhivotovsky
Laboratory of investigation of apoptosis mechanisms, Faculty of Fundamental Medicine, Lomonosov Moscow State University, Russia
Multiple program cell death modalities operate in both uni- and multicellular organisms. Research carried out during the past more than forty years has revealed that apoptosis is not the only mode of cell death involved in the regulation of tissue homeostasis and the removal of unwanted cells in biological organisms. While the molecular pathways of apoptosis and pathological necrosis are now relatively well established, the precise mechanisms of other cell death modalities, and their cross-talk, require additional study.
The main goal of our research project was to uncover additional molecular mechanisms of apoptosis regulation, to understand the cross-talk between apoptosis and other modes of cell death and their role in tumor resistance to treatment.
During development of the project we:
• established a new model of caspase-8 activation at the DISC via DED chains;
• found that PIDDosome is not only one platform initiating DNA damage-induced apoptosis;
• found the putative new caspase-2 activating platforms;
• established an importance of mitochondrial targeting for elimination of tumor cells otherwise resistant to treatment;
• uncovered the mechanisms of cell death stimulation by alpha-tocopheryl succinate;
• demonstrated the ability of alpha-tocopheryl succinate to overcome resistance of tumors under hypoxic conditions;
• revealed the importance of mutations in cytochrome c for mitochondrial vital functions and cell death initiation;
• found that suppression of autophagy in NSCLC cells with active basal autophagy reduced their proliferation without significant effect on the cell-cycle distribution;
• established that autophagy suppression leads to inhibition of NSCLC cell proliferation and sensitizes them to cisplatin-induced caspase-dependent and -independent apoptosis by stimulation of ROS formation.
In addition we organized the first special course in Russia “Programmed cell death in biology and medicine”, which includes both theoretical and practical lessons to which more than 150 young researchers from Moscow and other Universities were attended. We also organized an international conference to which world leading scientists in the field were participating.
Our achievements and future plans will be discussed.