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

L-F Dong1, P Low, J C Dyason

  • 1Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.

Oncogene
|April 1, 2008
PubMed

Insights

Alpha-tocopheryl succinate (alpha-TOS) selectively induces cancer cell death by inhibiting complex II (CII) and increasing reactive oxygen species (ROS). This study identifies CII as a novel therapeutic target for cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Alpha-tocopheryl succinate (alpha-TOS) induces apoptosis in cancer cells, linked to reactive oxygen species (ROS) accumulation.
  • The precise molecular target of alpha-TOS remains unidentified.

Purpose of the Study:

  • To identify the molecular target of alpha-tocopheryl succinate (alpha-TOS).
  • To elucidate the mechanism by which alpha-TOS induces apoptosis in cancer cells.
  • To evaluate complex II (CII) as a potential therapeutic target in cancer.

Main Methods:

  • Biochemical assays to measure succinate dehydrogenase (SDH) activity.
  • Molecular modeling to analyze alpha-TOS interaction with ubiquinone-binding sites.
  • Utilizing CybL-mutant cells and siRNA knockdown for complex II (CII) dysfunction.
  • Reconstitution experiments to restore CII function.

Main Results:

  • Alpha-tocopheryl succinate (alpha-TOS) inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by binding to ubiquinone (UbQ)-binding sites (Q(P) and Q(D)).
  • Alpha-TOS exhibits strong binding affinity to the Q(P) and Q(D) sites, comparable or superior to UbQ.
  • Cells with dysfunctional CII (CybL-mutant or siRNA knockdown) resist alpha-TOS-induced ROS accumulation and apoptosis.
  • Restoring functional CII restores sensitivity to alpha-TOS.

Conclusions:

  • Complex II (CII) is identified as the molecular target of alpha-tocopheryl succinate (alpha-TOS).
  • Alpha-TOS displaces ubiquinone (UbQ) in CII, leading to ROS generation and apoptosis.
  • Complex II (CII), a tumor suppressor, represents a novel target for cancer therapy.

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