alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

作者：Dong L F; Low P; Dyason J C; Wang X F; Prochazka L; Witting P K; Freeman R; Swettenham E; Valis K; Liu J; Zobalova R; Turanek J; Spitz D R; Domann F E; Scheffler I E; Ralph S J^*; Neuzil J

来源：Oncogene, 2008, 27(31): 4324-4335.

DOI：10.1038/onc.2008.69

• alpha-tocopheryl succinate
• complex II
• ubiquinonebinding sites
• reactive oxygen species
• apoptosis
• anti-cancer drug target

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 a- TOS compared to that of UbQ for the QP and QD 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.

• 出版日期2008-7-17