論文 - 詳細
| RRC ID | 83300 |
|---|---|
| 著者 | Naghdi S, Mishra P, Roy SS, Weaver D, Walter L, Davies E, Antony AN, Lin X, Moehren G, Feitelson MA, Reed CA, Lindsten T, Thompson CB, Dang HT, Hoek JB, Knudsen ES, Hajnóczky G. |
| タイトル | VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes. |
| ジャーナル | Nat Commun |
| Abstract |
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. |
| 巻・号 | 16(1) |
| ページ | 2416 |
| 公開日 | 2025-3-11 |
| DOI | 10.1038/s41467-025-56898-4 |
| PII | 10.1038/s41467-025-56898-4 |
| PMID | 40069152 |
| PMC | PMC11897174 |
| MeSH | Animals Apoptosis / drug effects BH3 Interacting Domain Death Agonist Protein* / genetics BH3 Interacting Domain Death Agonist Protein* / metabolism Carcinoma, Hepatocellular* / genetics Carcinoma, Hepatocellular* / metabolism Carcinoma, Hepatocellular* / pathology Cell Line, Tumor Hepatocytes* / metabolism Humans Liver Neoplasms* / genetics Liver Neoplasms* / metabolism Liver Neoplasms* / pathology Male Mice Mitochondria, Liver* / metabolism Myeloid Cell Leukemia Sequence 1 Protein / genetics Myeloid Cell Leukemia Sequence 1 Protein / metabolism TNF-Related Apoptosis-Inducing Ligand / metabolism TNF-Related Apoptosis-Inducing Ligand / pharmacology Voltage-Dependent Anion Channel 2* / genetics Voltage-Dependent Anion Channel 2* / metabolism bcl-2 Homologous Antagonist-Killer Protein* / genetics bcl-2 Homologous Antagonist-Killer Protein* / metabolism |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Blogs |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HuH-7(RCB1366) |