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

Our plain-English summary of Silencing VDAC1 to Treat Mesothelioma Cancer: Tumor Reprograming and Altering Tumor Hallmarks, by S.K. Pandey, R. Machlof-Cohen, M. Santhanam, et al (Biomolecules, 2022).

The study

• Authors: S.K. Pandey, R. Machlof-Cohen, M. Santhanam, A. Shteinfer-Kuzmine, V. Shoshan-Barmatz
• Journal: Biomolecules
• Published: 2022;12(7)
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory and animal study. It did not study asbestos exposure or people exposed to asbestos. The authors tested whether reducing a mitochondrial protein called VDAC1 with a small interfering RNA (si-m/hVDAC1-B) affected mesothelioma. In a purchased tissue array (8 normal, 2 benign and 52 mesothelioma samples), VDAC1 levels were markedly higher in tumor tissue. In public gene-expression data (63 patients with low/medium and 22 with high VDAC1), high VDAC1 was associated with low survival. In a human (H226) and a mouse (AB1) mesothelioma cell line, the siRNA lowered VDAC1 by about 70% and 90% at 72 hours and significantly inhibited cell growth. In mice with implanted tumors (6 per group), H226 tumors injected with the siRNA grew from about 150 to 324 mm3, against about 150 to 1010 mm3 with a control siRNA, an 80% inhibition. AB1 tumor growth was inhibited by 60%. Treated H226 tumors showed lower levels of metabolic enzymes, cancer stem cell markers and several inflammation markers. Activated caspase-1, however, rose more than threefold. The authors concluded this might be a promising therapeutic approach for mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using cell lines, a commercial tissue microarray, publicly available patient survival data, and mouse tumor models (animal experiment)
• Who was studied: Tissue microarray samples (8 normal, 2 benign, 52 mesothelioma). Human H226 and mouse AB1 mesothelioma cell lines. Mice with implanted tumors: nude mice with H226 cells and BALB/c mice with AB1 cells, 6 per treatment group. Public gene-expression data on 85 mesothelioma patients (63 low/medium, 22 high VDAC1).
• Exposure: No asbestos exposure was studied. The intervention was a VDAC1-silencing siRNA (si-m/hVDAC1-B), compared with a non-targeting control siRNA (si-NT). In mice it was injected into the tumors every three days, to a final concentration of 100 nM.
• Main results:
  • In the tissue microarray, VDAC1 expression was markedly higher in mesothelioma tumor tissue than in healthy tissue.
  • In publicly available gene expression data on mesothelioma patients, high VDAC1 levels were associated with low survival rates.
  • The survival analysis began with 63 patients with low/medium VDAC1 and 22 with high VDAC1, p = 0.0001.
  • In cell culture, VDAC1 decreased by about 70% in H226 cells and about 90% in AB1 cells at 72 hours after siRNA treatment.
  • si-m/hVDAC1-B significantly inhibited cell proliferation in both the human and the mouse cell lines.
  • In H226 tumors in mice, control-treated tumors grew from about 150 to 1010 mm3, while si-m/hVDAC1-B-treated tumors grew from about 150 to 324 mm3, an 80% inhibition of tumor growth.
  • In AB1 tumors in mice, tumor growth inhibition relative to the control group was 60%.
  • Staining for the proliferation marker Ki-67 decreased by about 85% in treated H226 tumors.
  • Metabolism-related proteins (HK-I, LDH, citrate synthase, ATP synthase subunit 5A, Glut-1) were highly reduced in treated H226 tumors compared with control-treated tumors.
  • In H226 cells in culture, the stem cell marker Sox2 decreased significantly (40–60%), while Oct4 did not change significantly.
  • In treated H226 tumors, both Oct4 and Sox2 decreased drastically compared with control-treated tumors.
  • In treated H226 tumors, the inflammation-related proteins TNF-α and activated NF-κB decreased.
  • In treated H226 tumors, activated caspase-1 increased more than threefold, while IL-1β and NRLP3 were reduced.
• The authors' conclusion: The authors concluded that VDAC1 depletion might be a promising therapeutic approach for mesothelioma and various cancers.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Asbestos Exposure, Inflammation, STEM, Tumor Microenvironment.

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