Journal article
α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II
Oncogene, Vol.27(31), pp.4324-4335
07/17/2008
DOI: 10.1038/onc.2008.69
PMCID: PMC2668987
PMID: 18372923
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 (Q
P
and Q
D
, 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 Q
P
and Q
D
sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and undergo 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.
Details
- Title: Subtitle
- α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II
- Creators
- Lan-Feng Dong - Apoptosis Research Group, Griffith University, Southport, Qld, AustraliaPauline Low - Genomic Research Centre, School of Medical Science, Griffith University, Southport, Qld, AustraliaJeffrey C Dyason - Institute for Glycomics, Griffith University, Southport, Qld, AustraliaXiu-Fang Wang - Apoptosis Research Group, Griffith University, Southport, Qld, AustraliaLubomir Prochazka - Department of Immunology, Veterinary Research Institute, Brno, Czech RepublicPaul K Witting - ANZAC Medical Research Institute, Concord Hospital, Concord, Sydney, NSW, AustraliaRuth Freeman - Apoptosis Research Group, Griffith University, Southport, Qld, AustraliaEmma Swettenham - Apoptosis Research Group, Griffith University, Southport, Qld, AustraliaKarel Valis - Molecular Therapy Group, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech RepublicJi Liu - Apoptosis Research Group, Griffith University, Southport, Qld, AustraliaRenata Zobalova - Apoptosis Research Group, Griffith University, Southport, Qld, AustraliaJaroslav Turanek - Department of Immunology, Veterinary Research Institute, Brno, Czech RepublicDoug R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USAFrederick E Domann - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USAImmo E Scheffler - Division of Biology, University of California, San Diego, CA, USAStephen J Ralph - Genomic Research Centre, School of Medical Science, Griffith University, Southport, Qld, AustraliaJiri Neuzil - Apoptosis Research Group, Griffith University, Southport, Qld, Australia
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.27(31), pp.4324-4335
- DOI
- 10.1038/onc.2008.69
- PMID
- 18372923
- PMCID
- PMC2668987
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Language
- English
- Date published
- 07/17/2008
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Surgery; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984047780802771
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