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

Oncogene. 2008 Jul 17;27(31):4324-35. doi: 10.1038/onc.2008.69. Epub 2008 Mar 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Binding Sites*
  • Cell Line, Tumor
  • Electron Transport Complex II / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Reactive Oxygen Species*
  • Tocopherols
  • Ubiquinone / chemistry*
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • respiratory complex II
  • Ubiquinone
  • Vitamin E
  • Electron Transport Complex II
  • Tocopherols