α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II
| Autor: | Renata Zobalova, Jiri Neuzil, Paul K. Witting, Jaroslav Turánek, Jeffrey Clifford Dyason, Emma Swettenham, Ji Liu, Lubomir Prochazka, Pauline Low, Stephen John Ralph, Immo E. Scheffler, Karel Valis, Ruth Freeman, Lan-Feng Dong, Xiu-Fang Wang, Doug Spitz, Frederick E. Domann |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Cancer Research Protein Conformation Ubiquinone Tocopherols Antineoplastic Agents Apoptosis macromolecular substances Mitochondrion medicine.disease_cause Article Mice Cell Line Tumor Genetics medicine Animals Humans Vitamin E Molecular Biology Ubiquinone binding chemistry.chemical_classification Reactive oxygen species Binding Sites biology Electron Transport Complex II Succinate dehydrogenase Molecular biology Mitochondria Gene Expression Regulation Biochemistry chemistry Cancer cell biology.protein Reactive Oxygen Species Carcinogenesis |
| Zdroj: | Oncogene. 27:4324-4335 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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