A59
Specific inhibition of mitochondrial respiratory chain complex II by anti-cancer drugs leads to apoptosis induction
Anthony LeMarie, Stefan Grimm
Imperial College London, Div. Investigative Sciences, London, UK
Through a genetic high-throughput screen, our group characterized various proapoptotic genes, notably SDHC (Succinate Dehydrogenase C), a membrane-anchoring subunit of respiratory chain complex II (succinate:ubiquinone oxidoreductase, SQR). This complex is also a component of the tricarboxylic acid cycle (TCA) and catalyzes the oxidation of succinate to fumarate by SDHA (SDH activity). We previously demonstrated that SDHC, a tumour suppressor protein, is part of a major apoptosis sensor, since numerous anti-cancer drugs inhibit complex II for apoptosis induction. In the present study, we have addressed the biochemical nature of this complex II inhibition.
We measured in parallel SDH activity and the total SQR activity in Hela cells treated with different anti-cancer drugs and showed that drug-triggered apoptosis is preceded by an inhibition of SQR activity without SDH alteration. We also assessed the effects of two direct inhibitors of complex II: 3-nitropropionate (3NP), which inhibits SDHA-linked SDH activity, and thenoyltrifluoroacetone (TTFA), which blocks the ubiquinone-binding site in the SDHC/SDHD subunits. We observed that 3NP inhibited equally both SDH and SQR activities. In contrast, TTFA led to an inhibition of SQR without impairing SDH activity, as for anti-cancer drugs. Moreover, TTFA, but not 3NP, was able to induce both superoxide production and apoptosis, which are significantly blocked by antioxidants and specific SDH or TCA inhibitors.
So far, our results suggest that TTFA or numerous anti-cancer drugs lead to specific complex II inhibition for ubiquinone reduction without SDH inhibition, allowing an electron leak between these two enzymatic sites, leading to superoxide production and apoptosis.
