Silencing VDAC1 to Treat Mesothelioma Cancer: Tumor Reprograming and Altering Tumor Hallmarks

Abstract

Mesothelioma, an aggressive cancer with a poor prognosis, is linked to asbestos exposure. However, carbon nanotubes found in materials we are exposed to daily can cause mesothelioma cancer. Cancer cells reprogram their metabolism to support increased biosynthetic and energy demands required for their growth and motility. Here, we examined the effects of silencing the expression of the voltage-dependent anion channel 1 (VDAC1), controlling the metabolic and energetic crosstalk between mitochondria and the rest of the cell. We demonstrate that VDAC1 is overexpressed in mesothelioma patients; its levels increase with disease stage and are associated with low survival rates. Silencing VDAC1 expression using a specific siRNA identifying both mouse and human VDAC1 (si-m/hVDAC1-B) inhibits cell proliferation of mesothelioma cancer cells. Treatment of xenografts of human-derived H226 cells or mouse-derived AB1 cells with si-m/hVDAC1-B inhibited tumor growth and caused metabolism reprogramming, as reflected in the decreased expression of metabolism-related proteins, including glycolytic and tricarboxylic acid (-)cycle enzymes and the ATP-synthesizing enzyme. In addition, tumors depleted of VDAC1 showed altered microenvironments and inflammation, both associated with cancer progression. Finally, tumor VDAC1 silencing also eliminated cancer stem cells and induced cell differentiation to normal-like cells. The results show that silencing VDAC1 expression leads to reprogrammed metabolism and to multiple effects from tumor growth inhibition to modulation of the tumor microenvironment and inflammation, inducing differentiation of malignant cells. Thus, silencing VDAC1 is a potential therapeutic approach to treating mesothelioma.

Voltage-Dependent Anion Channel 1 Expression in Oral Malignant and Premalignant Lesions

“…In principle, VDAC’s involvement in mitochondria-mediated cell death can be used for cancer treatment but this option was not yet fully materialized [ 32 ]. To date, the only positive results were achieved when VDAC1 silencing was applied to the treatment of mesothelioma [ 33 ].…”

“…Cisplatin, 5-azacytidine, and 5-fluorouracil, which are currently used as chemotherapy drugs against OSCC do not influence VDAC1 behavior [ 48 , 49 , 50 ]. Silencing VDAC1 is used for the treatment of mesothelioma and some other tumors [ 19 , 33 ] but this approach is inapplicable to OSCC because VDAC1′s expression is decreased already. Therefore, further research might concentrate on the implementation of nano-drug delivery systems and intelligent delivery systems to treat OSCC [ 51 ].…”

Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer

“…Silencing Reduces Cell Viability, Proliferation, Mitochondrial Membrane Potential, and ATP Levels in Bladder Cancer Cell Lines Next, we tested the effects of si-m/hVDAC1-B, recognizing both mouse and human VDAC1 [24] on the proliferation and survival of the BC cell lines, UM-UC3 and HTB-5. si-m/hVDAC1-B decreased VDAC1 expression by about 80%, relative to si-NT treated cells (Figure 2A,B).…”

Increase in primary cilia number and length upon VDAC1 depletion contributes to attenuated proliferation of cancer cells

“…VDAC1 is the best studied for its role in cellular bioenergetics and its high expression is associated with low-survival rate in many cancers suggesting it as an attractive prognostic marker and therapeutic target [14,29,30,[42][43][44]. We first identified VDAC1 to localize to centrosomes/basal bodies, and to regulate ciliogenesis [10].…”