Cancer cells acquire a common set of properties, including increased proliferation, metabolic re-programing, cell survival strategies and anti-apoptotic mechanisms. These processes involve changes in key oncogenes and non-oncogenes essential for cancer cell survival. The ultimate goal in cancer therapy is therefore, to either reverse these properties and/or to target them as tumor-specific liabilities. The multifunctional mitochondrial protein VDAC1 is a mitochondria gatekeeper and a convergence point for various cell survival and death signals. VDAC1 acts at a “bottleneck” position, controlling the metabolic and energy functions of mitochondria and the cell. Most cancer cells undergo metabolic reprograming known the “Warburg effect”, a phenomenon that also provides tumors with precursors for the biosynthesis of nucleic acids, phospholipids, fatty acids, cholesterol and porphyrins. VDAC1 is over-expressed in many cancer types and thus represents an attractive target for cancer therapy.
A single (nanomolar) VDAC1 silencing siRNA, resulted in decreased energy production and inhibition of cancer cell growth in 30 tested tumor cell lines in vitro. Abrogation of VDAC1 expression reduced cellular ATP levels and inhibited the growth of cancerous but not non-cancerous cells, regardless of their origin or mutational status. Similar results were also demonstrated in-vivo using lung cancer (LC) and breast cancer (BC) and glioblastoma multiforme (GBM) mouse models. In xenograft mouse model, silencing human VDAC1 expression in LC, BC and GBM via specific si-hVDAC1, resulted in a multi-pronged attack on cancer hallmarks, reversing oncogenic properties via cancer-reprogrammed metabolism, resulting in inhibited cell proliferation, tumor growth, invasiveness, tumor-associated macrophage (TAM) presence and sharp decrease of angiogenesis. VDAC1 depletion also targeted radio- and chemo-resistant cancer stem cells, leading to their differentiation into mature cells that cannot replicate, thereby preventing tumor recurrence.
- Prof. Shoshan-Barmatz is a leader in the research of VDAC1.
- VDAC1 depletion can substitute for several anti-cancer modalities. si-VDAC1 treatment inducing reprogramed metabolism should increase sensitivity to other anti-cancer treatments and can thus be given in combinations.
- VDAC1 silencing also eliminated cancer stem cells and reprogramed tumor cells to advanced differentiated states, thus it may also prevent tumor recurrence.
Patent application filed.
Prof. Varda Shoshan-Barmatz, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel