Research Group Boris Zhivotovsky
Molecular mechanisms of cell death and implication in disease
The research in our group is divided into two parts:
- basic research, which is focused on investigation of the mechanisms of DNA damage-mediated cell death and the mitochondrial involvement in cell death; and
- applied research, which is focused on the understanding of the function of cell death machinery in human tumor cells resistant to anticancer treatment and to take attempt to modify the efficiency of the killing of these tumors.
Although, for many years DNA damage was thought to kill cells via apoptosis or necrosis, studies during the last few years have revealed that DNA damage might also lead to autophagy or mitotic catastrophe, followed by apoptosis or necrosis. The molecular mechanisms of the decision-making process are the subject of our intense investigation. Therefore, in the first part we investigating the mechanisms of 5-FU-mediated cell death, the details of protein complexes activated in response to this drug and signaling, leading to cell death.
For many years one of our interests was focused on analysis of one of the most “magic” enzyme from caspase family, namely, caspase-2. Nowadays became clear that in addition to its role in cell death caspase-2 fulfil various non-apoptotic functions. We are continuing the studies on both apoptotic and non-apoptotic functions of caspase-2, as well as its activation in different intracellular compartments.
It is known that mitochondria act as a switch-board during cell death via release of proteins from the intermembrane space to the cytosol. Mechanisms of this release are in the focus of our research. Moreover, we are trying to understand the role of mitochondria in mitotic catastrophe. Evaluation of the reactive oxygen species (ROS) generation by mitochondria as well as investigation of the effects of endo- and exogenously produced ROS on cellular energy metabolism is in the focus of our research.
In the second part we identifying the genes and proteins expressed or modified in a panel of small- (SCLC) and non-small (NSCLC) cell lung carcinomas, with different sensitivity to treatment using genomics and proteomics techniques, and monitoring the changes in genes and proteins expression in response to chemotherapy drugs or radiation in most representative cell lines.
One of our goals is to take an attempt to modify the efficiency of the killing of these tumors. Recent work in our and other group has shown that interplay between various cell deaths modalities can help in this attempt. For example, inhibition of autophagy was able to sensitize NSCLC cells to apoptosis and modulation of autophagy in response to treatment with either cytotoxic compounds or therapeutic drugs plays a crucial role in a cell fate decision. These experiments will be continuing.
Keeping in mind our experience in mitochondrial research and accumulating evidence concerning their role in cancer development one of our projects is focusing on targeting energy producing pathways as a promising strategy in anticancer therapy. Based on our previous results and preliminary data, specific attention will be given to compounds sensitizing tumor cells to treatment through inhibition of glycolysis or oxidative phosphorylation.
Our research is performing in tight collaboration with several Departments at Karolinska Institutet, among them are Cancer Center Karolinska and Institute of Microbiology and Tumor Biology.