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α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

Oncogene volume 27, pages 4324–4335 (2008)Cite this article

Abstract

α-Tocopheryl succinate (α-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of α-TOS has not been identified. Here, we show that α-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (QP and QD, respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of α-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 α-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to α-TOS. We propose that α-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.

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Acknowledgements

We thank Professor RAJ Smith for providing MitoQ, and Professor RK Ralph and Professor JW Eaton for critical reading of the manuscript. This work was supported in part by grants from the National Breast Cancer Foundation, the Queensland Cancer Fund and the Australian Research Council (Discovery Grant DP0453372 to JN and Fellowship DP0343325 to PKW), and a grants from the Academy of Sciences of the Czech Republic (IAA500520702 and KAN2005207203 to JN), and by a grant from the Ministry of Agriculture of the Czech Republic (MZE 0002716201 to JT). DRS and FED were supported by NIH grants RO1-CA100045 (DRS) and NIH RO1-CA73612 (FED).

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  1. L Prochazka: Visiting student with the Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.

Authors and Affiliations

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

    L-F Dong, X-F Wang, R Freeman, E Swettenham, J Liu, R Zobalova & J Neuzil

  2. Genomic Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia

    P Low & S J Ralph

  3. Institute for Glycomics, Griffith University, Southport, Queensland, Australia

    J C Dyason

  4. Department of Immunology, Veterinary Research Institute, Brno, Czech Republic

    L Prochazka & J Turanek

  5. ANZAC Medical Research Institute, Concord Hospital, Concord, Sydney, New South Wales, Australia

    P K Witting

  6. Molecular Therapy Group, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic

    K Valis, R Zobalova & J Neuzil

  7. Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA

    D R Spitz & F E Domann

  8. Division of Biology, University of California, San Diego, CA, USA

    I E Scheffler

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Dong, LF., Low, P., Dyason, J. et al. α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 27, 4324–4335 (2008). https://doi.org/10.1038/onc.2008.69

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