Background

Ca2+ is a signaling molecule that carries information in virtually all processes important to cell life, as well as participating in cell death. My laboratory focuses on the structure-function of proteins involved in either Ca2+ homeostasis or regulating mitochondrial function in cell life and death. Understanding the biological processes regulated by Ca2+ requires identification of the proteins involved and their control mechanisms. A second major focus addresses mitochondria, the "power house" of the cell that also plays a key role in programmed cell death - apoptosis. In apoptosis, the mitochondrial protein VDAC, regulating cellular energy metabolism, serves as a site for apoptotic signaling. Since VDAC functions at a checkpoint of cell life and death and because apoptosis is rendered ineffective in cancer cells, selective induction of VDAC-mediated apoptosis in carcinogenic tissues represents a potential cancer therapy.

Current Projects

A. The activity of calcium is mediated by its interaction with a specific site in responsive proteins. While numerous Ca2+-dependent activities are known, many of the proteins responsible for these activities remain unidentified. Our approach to identify such proteins involved the synthesis of a novel photoreactive reagent, AzRu, that interacts specifically and either reversibly or irreversibly with Ca2+-binding proteins. AzRu offers new strategies not only for identification of Ca2+-binding proteins and their Ca2+-binding sites, but also a novel tool for their purification, leading to the development of bio-sensor chips and diagnosis of diseases that result from alterations in Ca2+-binding proteins.

B. Given that mitochondria play a central role in the execution of apoptosis and that VDAC is the gatekeeper of mitochondrial function and dysfunction, we have generated potent, specific and effective VDAC-based cancer therapies facilitating the death or arresting the growth of cancer cells. Three novel strategies for cancer therapy involving specific targeting of VDAC to cancer cells are being followed:

1. Triggering apoptosis by targeting VDAC over-expression in cancer cells- We have shown that over-expression of VDAC in many cancer cell lines induces cell death. Thus, targeting VDAC over-expression could specifically induce apoptosis in cancer cells.

2. Arresting cell proliferation by down-regulation of VDAC expression- We have demonstrated that suppression of VDAC expression in cancer cells results in arrested cell proliferation due to an interrupted supply of fuel to the high energy-demanding cancer cells.

3. Targeting VDAC-based peptides to minimize the self-defense mechanisms of cancer cells- We have identified VDAC sequences involved in its interaction with anti-apoptotic proteins. Targeting VDAC-based peptides to tumor cells, known to over-express anti-apoptotic proteins, would minimize the self-defense mechanisms of the cancer cells, thereby promoting apoptosis and increasing sensitivity to chemotherapy. Thus, by packaging and specific targeting of VDAC1-based agents to cancer cells, we expect to develop novel cancer therapies.

Recent Publications

Ph.D. Weizmann Institute of Science