Former NIBN Director
Ph.D.: Weizmann Institute of Science, Israel
Post-doctorate: University of Wisconsin-Madison, USA and
University of Toronto, Canada
Position: Professor, Former NIBN Director
Department of Life Sciences
Faculty of Natural Sciences
Novel approaches to cancer therapy
Many cancer cells undergo re-programming of their metabolism and develop cell survival strategies involving anti-apoptosis defense mechanisms, a hallmark of the majority of cancer types. Found at the outer mitochondrial membrane, the voltage-dependent anion channel (VDAC) assumes a crucial position in the cell serving as a gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell, and is involved in apoptosis. VDAC is the proposed target for the pro- and anti-apoptotic Bcl2-family of proteins, as well as functioning in the release of apoptotic proteins located in the inter-membranal space. Thus VDAC is considered a key player in cell metabolism and regulation of mitochondria-mediated apoptosis. As such, VDAC1 represents an excellent target to approach in order to impair the re-programmed metabolism of cancer cells and their capability to evade apoptosis.
Given that mitochondria play a central role in the execution of apoptosis and that VDAC1 is the gatekeeper of mitochondrial function and dysfunction, we have generated specific, potent and highly effective VDAC1-based cancer therapies that facilitate the death of cancer cells or arrest of cell growth. Five novel strategies towards developing cancer therapies involving VDAC1 are currently being pursued in my laboratory:
1. Targeting anti-apoptotic proteins using VDAC1-based peptides to minimize the self-defense mechanisms of cancer cells, known to overexpress anti-apoptotic proteins. We have identified VDAC1 sequences involved in interactions between VDAC1 and anti-apoptotic proteins and demonstrated that VDAC1-based peptides prevent the anti-apoptotic proteins’ activity, disturb cell energy homeostasis and lead to apoptotic cell death specifically. In-vitro, such peptides were shown to be active in a variety of cancer cell lines regardless of the carried mutations and inhibited glioblastoma tumor growth in-vivo.
2. Arresting cell proliferation by down-regulation of VDAC1 expression – Our results have shown that suppression of VDAC1 expression by a single siRNA arrested cell proliferation due to interrupted energy and metabolite supply to the high energy-demanding cancer cells. We have demonstrated proof-of-concept in animal models with cervical and lung cancers.
3. We have demonstrated that VDAC1 oligomerization is a general mechanism that is common to many apoptosis inducers, acting via different pathways. We have developed a high throughput screening (HTS) assay for modulators of VDAC1 oligomerization and have identified pro- and anti-apoptotic drugs acting via modulation of VDAC1 oligomerization. The aim is to develop molecules that, a) promote VDAC1 oligomerization andthe subsequent apoptotic cell death, thereby serving as anti-cancer therapeutics, and b) inhibitVDAC1 oligomerization thereby preventing cell death and allow the rescue of nerve cells in neurodegenerative diseases.
4. We have demonstrated an increase in VDAC1 expression levels following apoptosis induction by various agents, as well as the correlation between drug efficacy and VDAC1 expression level. We propose a new concept according to which several apoptosis-inducing agents and conditions act by up-regulating VDAC1 expression in a Ca2+-dependent manner, leading to VDAC1 assembly into high oligomeric structures and thereby to cell death. Further investigations y of this novel mechanism may provide a unique platform for developing a new class of anti-cancer drugs.
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. Nat. Ac. Sci. USA 386:73-83.
Arzoine L., Zilberberg N., Ben-Romano R. and Shoshan-Barmatz V. (2009). Voltage-Dependent Anion Channel-1-based peptides interact with and prevent hexokinase anti-apoptotic activity. J. Biol. Chem. 284:3946-3955.
Shoshan-Barmatz V., de Pinto P., Markus Zweckstetter M., Raviv, Z., Keinan N. and Arbel N. (2010). VDAC, a multi-functional mitochondrial protein regulating both cell life and death. Molecular Aspects of Medicine. 31:227-286 (invited review).
Arbel N., Ben-Hail D. and Shoshan-Barmatz V. (2012). Mediation of the anti-apoptotic activity of BCL-XL upon interaction with VDAC1. J. Biol. Chem. 287(27):23152-23161.
Shoshan-Barmatz V., Mizrachi D. and Keinan K. (2013). Oligomerization of the mitochondrial protein VDAC1: From structure to function and cancer therapy. Prog. Mol. Biol. Transl. Sci. 117:303-334.
Prezma T., Shteinfer A., Admoni L., Raviv Z., Levi l. and Shoshan-Barmatz V. (2013). VDAC1-based peptides: Novel pro-apoptotic agents and potential therapeuticsfor B cell chronic lymphocytic leukemia. Cell Death and Disease, e809. doi: 10.1038/cddis.2013.316. PMID:24052077