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VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes
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VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes
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Journal Article
VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes
2025
Overview
Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.
In this study, the authors show that low levels of VDAC2 and Bak in hepatocyte mitochondria make them resistant to cell death induced by truncated Bid (tBid), while increased VDAC2 and Bak in liver cancer cells allow specific targeting by combinations of tBid activators and Mcl-1 inhibitors.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 13/2
/ 13/44
/ 13/95
/ 14
/ 14/19
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/ 38
/ 49
/ 59
/ 59/5
/ 96
/ 96/63
/ Animals
/ bcl-2 Homologous Antagonist-Killer Protein - genetics
/ bcl-2 Homologous Antagonist-Killer Protein - metabolism
/ BH3 Interacting Domain Death Agonist Protein - metabolism
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - genetics
/ Carcinoma, Hepatocellular - metabolism
/ Carcinoma, Hepatocellular - pathology
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Liver Neoplasms - drug therapy
/ Liver Neoplasms - metabolism
/ Mice
/ Mitochondria, Liver - metabolism
/ Proteins
/ Science
/ TNF-Related Apoptosis-Inducing Ligand - pharmacology
/ Tumors
