RESUMEN
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.
Asunto(s)
Apoptosis , Sitios de Unión , Complejo II de Transporte de Electrones/metabolismo , Regulación de la Expresión Génica , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno , Ubiquinona/química , Vitamina E/análogos & derivados , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Ratones , Modelos Moleculares , Conformación Proteica , Tocoferoles , Vitamina E/farmacologíaRESUMEN
Tedious lectures about the dangers of smoking are a thing of the past for 10th graders in two Flint-are high schools. These students will learn to kick the habit this fall through an interactive high tech health class, created through a partnership between the schools, McLaren Health Care Corporation and Ameritech.
