title: Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II.
abstract: Alpha-tocopheryl succinate (alpha-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of alpha-TOS has not been identified. Here, we show that alpha-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q(P) and Q(D), respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of alpha-TOS compared to that of UbQ for the Q(P) and Q(D) sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of alpha-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to alpha-TOS. We propose that alpha-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.
authors: Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.
authors: L-F
authors: LF
authors: Dong
authors: P
authors: P
authors: Low
authors: J C
authors: JC
authors: Dyason
authors: X-F
authors: XF
authors: Wang
authors: L
authors: L
authors: Prochazka
authors: P K
authors: PK
authors: Witting
authors: R
authors: R
authors: Freeman
authors: E
authors: E
authors: Swettenham
authors: K
authors: K
authors: Valis
authors: J
authors: J
authors: Liu
authors: R
authors: R
authors: Zobalova
authors: J
authors: J
authors: Turanek
authors: D R
authors: DR
authors: Spitz
authors: F E
authors: FE
authors: Domann
authors: I E
authors: IE
authors: Scheffler
authors: S J
authors: SJ
authors: Ralph
authors: J
authors: J
authors: Neuzil
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D042963:Electron Transport Complex II / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D017382:Reactive Oxygen Species; D024505:Tocopherols; D014451:Ubiquinone / Q000737:chemistry*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C478189:respiratory complex II; D014451:Ubiquinone; D014810:Vitamin E; D042963:Electron Transport Complex II; D024505:Tocopherols