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A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells

Li Huang1, Junjie Han2, Danya Ben-Hail3

  • 1From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, the University of the Chinese Academy of Sciences, Beijing 100049, China.

The Journal of Biological Chemistry
|August 9, 2015
PubMed

Insights

A new compound, cyathin-R, triggers programmed cell death (apoptosis) by activating the VDAC1 protein, even when key apoptosis proteins Bax and Bak are absent. This offers a potential cancer therapy for cells lacking Bax/Bak.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pharmacology

Background:

  • The proteins Bax and Bak are crucial for initiating apoptosis, a key cell death pathway.
  • Apoptosis can still occur even when Bax and Bak are absent, suggesting alternative mechanisms exist.

Purpose of the Study:

  • To investigate if the mitochondrial protein VDAC1 can mediate apoptosis independently of Bax and Bak.
  • To identify novel compounds that can induce apoptosis in a Bax/Bak-independent manner.

Main Methods:

  • Screening a fungal secondary metabolite library for compounds inducing apoptosis in Bax/Bak-deficient cells.
  • Utilizing VDAC1 inhibitors and gene silencing to confirm VDAC1's role.
  • Testing the compound's efficacy in a xenograft mouse model.

Main Results:

  • Cyathin-R, a novel cyathane diterpenoid, induced apoptosis in Bax/Bak-deficient cells by promoting VDAC1 oligomerization and subsequent cytochrome c release.
  • Inhibition of VDAC1 and Bcl-2 overexpression blocked cyathin-R-induced apoptosis.
  • VDAC1 silencing prevented cyathin-R-induced apoptosis.
  • Cyathin-R reduced tumor growth in a xenograft model.

Conclusions:

  • Cyathin-R activates apoptosis through a VDAC1-dependent pathway, independent of Bax and Bak.
  • This compound represents a potential therapeutic strategy for cancers with deficient Bax/Bak.
  • VDAC1-mediated apoptosis offers a target for novel anti-cancer drug development.
Keywords:
B-cell lymphoma 2 (Bcl-2)BaxBcl2cyathane diterpenoidmitochondrial apoptosisoligomerizationprotein cross-linkingvoltage-dependent anion channel (VDAC)

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