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VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes

Author

Listed:
  • Shamim Naghdi

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Piyush Mishra

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Soumya Sinha Roy

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • David Weaver

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Ludivine Walter

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Erika Davies

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Anil Noronha Antony

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Xuena Lin

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Gisela Moehren

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Mark A. Feitelson

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Christopher A. Reed

    (Thomas Jefferson University)

  • Tullia Lindsten

    (University of Pennsylvania
    Memorial Sloan Kettering Cancer Center)

  • Craig B. Thompson

    (University of Pennsylvania
    Memorial Sloan Kettering Cancer Center)

  • Hien T. Dang

    (Thomas Jefferson University)

  • Jan B. Hoek

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

  • Erik S. Knudsen

    (Thomas Jefferson University)

  • György Hajnóczky

    (Department of Pathology and Genomic Medicine and Thomas Jefferson University)

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.

Suggested Citation

  • Shamim Naghdi & Piyush Mishra & Soumya Sinha Roy & David Weaver & Ludivine Walter & Erika Davies & Anil Noronha Antony & Xuena Lin & Gisela Moehren & Mark A. Feitelson & Christopher A. Reed & Tullia L, 2025. "VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56898-4
    DOI: 10.1038/s41467-025-56898-4
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