title: A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells.
abstract: The pro-apoptotic Bax and Bak proteins are considered central to apoptosis, yet apoptosis occurs in their absence. Here, we asked whether the mitochondrial protein VDAC1 mediates apoptosis independently of Bax/Bak. Upon screening a fungal secondary metabolite library for compounds inducing apoptosis in Bax/Bak-deficient mouse embryonic fibroblasts, we identified cyathin-R, a new cyathane diterpenoid compound able to activate apoptosis in the absence of Bax/Bak via promotion of the VDAC1 oligomerization that mediates cytochrome c release. Diphenylamine-2-carboxilic acid, an inhibitor of VDAC1 conductance and oligomerization, inhibited cyathin-R-induced VDAC1 oligomerization and apoptosis. Similarly, Bcl-2 overexpression conferred resistance to cyathin-R-induced apoptosis and VDAC1 oligomerization. Silencing of VDAC1 expression prevented cyathin-R-induced apoptosis. Finally, cyathin-R effectively attenuated tumor growth and induced apoptosis in Bax/Bak-deficient cells implanted into a xenograft mouse model. Hence, this study identified a new compound promoting VDAC1-dependent apoptosis as a potential therapeutic option for cancerous cells lacking or presenting inactivated Bax/Bak.
authors.affiliation: From 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.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: the State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Han
authors.affiliation: the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, and.
authors.forename: Danya
authors.initials: D
authors.lastname: Ben-Hail
authors.affiliation: the State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Luwei
authors.initials: L
authors.lastname: He
authors.affiliation: From 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.
authors.forename: Baowei
authors.initials: B
authors.lastname: Li
authors.affiliation: From 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.
authors.forename: Ziheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: From 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.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From 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.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: the Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 30071, China.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, and vardasb@bgu.ac.il.
authors.forename: Varda
authors.initials: V
authors.lastname: Shoshan-Barmatz
authors.affiliation: the State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China, liuhw@im.ac.cn.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liu
authors.affiliation: From 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, chenq@ioz.ac.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D051381:Rats; D050995:Voltage-Dependent Anion Channel 1 / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D004224:Diterpenes; C494762:VDAC1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C007179:cyathins; D050995:Voltage-Dependent Anion Channel 1
keywords: B-cell lymphoma 2 (Bcl-2); Bax; Bcl2; cyathane diterpenoid; mitochondrial apoptosis; oligomerization; protein cross-linking; voltage-dependent anion channel (VDAC)