Ph.D.: Weizmann Institute of Science, Israel

Post-doctorate: University of Wisconsin-Madison, USA and

University of Toronto, Canada

Position: Professor, NIBN Director

Department of Life Sciences

Faculty of Natural Sciences

E-mail: vardasb@bgu.ac.il

Webpage:
http://cmsprod.bgu.ac.il/Eng/Teva/departments/LifeScience/FacultyMembers/Varda_Shoshan-Barmatz.htm

Novel approaches to cancer therapy and exploring Ca2+ as a bio-regulator

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 play 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 research

1. 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 identifying such proteins involves the synthesis of a novel photoreactive reagent, AzRu, that interacts specifically and either reversibly or irreversibly with Ca2+-binding proteins. AzRu offers not only new strategies 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.
2. 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 in 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 cells 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 – Our results have shown 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 antiapoptotic proteins. Targeting VDAC-based peptides to tumor cells, known to overexpress anti-apoptotic proteins, would minimize the self-defense mechanisms of the cancer cells, thereby promoting apoptosis and increasing sensitivity to chemotherapy.

Thus, by the packaging and specific targeting of VDAC1-based agents to cancer cells, we expect to develop novel cancer therapies.

Selected publications

Zaid H., Abu-Hamad S., Israelson A. and Shoshan-Barmatz V. (2005) The voltagedependent

anion channel modulates apoptotic cell death. Cell Death and Differentiation, 12:751-760.

Abu-Hamad S., Sivan S. and Shoshan-Barmatz V. (2006) The voltage-dependent anion channel down- and over- expression control cell’s life and death. Proc. Natl. Acad. Sci. USA, 386:73-83.

Israelson A., Zilberberg N. and Shoshan-Barmatz V. (2006) Azido ruthenium: A novel photoactivable probe for Ca2+- binding proteins. Nature Protocols, 1:111-117.