# (PQ5) Relevance of VDAC2 heterogeneity for hepatic tumor growth and targeting

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $398,508

## Abstract

PROJECT SUMMARY/ABSTRACT
Liver cancers with increasing frequency in the world have become the second cause of cancer related death;
however an important gap in current knowledge remains the molecular fingerprint and organization of
hepatocarcinoma/hepatoma cells which might allow their specific targeting. We found that the expression level
of two proteins, VDAC2 and Bak, that are central to a mitochondrial apoptosis pathway, is low in normal
hepatocytes and is increased during hepatic tumor progression. Furthermore, we also found that the pro-
apoptotic BH3-only Bcl-2 family protein, Bid induces mitochondrial apoptosis more efficiently in
hepatocarcinoma than in normal liver. This difference can be eliminated by VDAC2 silencing in
hepatocarcinoma cells, and by VDAC2 expression in normal hepatocytes but only if Bak isn’t knocked out. The
potential medical significance of the VDAC2-Bak heterogeneity is supported by human databases that show
upregulation of VDAC2 and Bak proteins in liver cancer. We have also documented both subcellular and cell-
to-cell differences in the tBid-Bak pathway. Finally, we have shown at least in cell culture, that
hepatocarcinoma cells can be selectively killed through the tBid-Bak pathway (using its activators and
suppressors of its inhibitor, Mcl-1 while normal hepatocytes are spared. We here, postulate that the
heterogeneity in VDAC2 and/or Bak abundance in the liver are important for hepatoma/
hepatocarcinoma (1) growth and (2) targeting by the combination of an Mcl-1 inhibitor drug and a cell
permeable hydrocarbon stapled Bid BH3 peptide. Heterogeneity is considered (1) within the cells among
individual mitochondria, (2) in each cell type among single cells, and (3) among the different cell types. To test
our hypothesis we have established a combination of genetic targeting, tumorigenesis in mouse, and
biochemical and microscopic imaging approaches. In the study we will focus on (1) assessing heterogeneity of
VDAC2, Bak and Bak-mediated OMM permeabilization in hepatocarcinoma cells and normal hepatocytes and
their dependence on VDAC2 expression and mitochondrial fusion; (2) determining whether increased
expression of VDAC2 through upregulation of Bak affects hepatoma/hepatocarcinoma progression; (3) testing
if activation of Bak by treatment with Mcl-1 inhibitor (S-63845) and a cell permeable hydrocarbon stapled Bid
peptide can be used to kill hepatocyte-derived tumors without damaging normal hepatocytes; and (4)
determining additional VDAC2-dependent proteins in hepatic tumor cells and to evaluate their heterogeneity in
the liver and their relevance for hepatoma/hepatocarcinoma growth. By addressing these points, our study will
provide clues to the contribution of mitochondrial heterogeneity to hepatic tumorigenesis and test a novel
tumor-selective targeting approach.

## Key facts

- **NIH application ID:** 10140306
- **Project number:** 5R01CA216254-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Gyorgy Hajnoczky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,508
- **Award type:** 5
- **Project period:** 2018-05-22 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140306

## Citation

> US National Institutes of Health, RePORTER application 10140306, (PQ5) Relevance of VDAC2 heterogeneity for hepatic tumor growth and targeting (5R01CA216254-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140306. Licensed CC0.

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