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

被引：246

作者：

Dong, L-F ^{[2
]}

Low, P. ^{[1
]}

Dyason, J. C. ^{[3
]}

Wang, X-F ^{[2
]}

Prochazka, L. ^{[4
]}

Witting, P. K. ^{[5
]}

Freeman, R. ^{[2
]}

Swettenham, E. ^{[2
]}

Valis, K. ^{[6
]}

Liu, J. ^{[2
]}

Zobalova, R. ^{[2
,6
]}

Turanek, J. ^{[4
]}

Spitz, D. R. ^{[7
]}

Domann, F. E. ^{[7
]}

Scheffler, I. E. ^{[8
]}

Ralph, S. J. ^{[1
]}

Neuzil, J. ^{[2
,6
]}

机构：

[1] Griffith Univ, Sch Med Sci, Genom Res Ctr, Southport, Qld 4215, Australia

[2] Griffith Univ, Sch Med Sci, Apoptosis Res Grp, Southport, Qld 4215, Australia

[3] Griffith Univ, Inst Glycom, Southport, Qld 4215, Australia

[4] Vet Res Inst, Dept Immunol, CS-62132 Brno, Czech Republic

[5] Concord Hosp, Med Res Inst, ANZAC, Sydney, NSW, Australia

[6] Acad Sci Czech Republ, Inst Biotechnol, Mol Therapy Grp, Prague, Czech Republic

[7] Univ Iowa, Dept Radiat Oncol, Free Rad & Radiat Biol Program, Iowa City, IA USA

[8] Univ Calif San Diego, Div Biol, San Diego, CA 92103 USA

来源：

ONCOGENE | 2008年 / 27卷 / 31期

关键词：

alpha-tocopheryl succinate; complex II; ubiquinonebinding sites; reactive oxygen species; apoptosis; anti-cancer drug target;

D O I：

10.1038/onc.2008.69

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 a- 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 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.

引用

页码：4324 / 4335

页数：12

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