Molecular mechanisms mediating the induction of apoptosis by chemopreventive selenium compounds.
PhD thesis, University of Glasgow.
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Using the cervical carcinoma cell line, HeLa, molecular mediators of selenium-induced apoptosis were investigated. These studies were later extended to biopsies of normal human oral mucosa cells (NOMCs) and human oral carcinoma cells (SCCs), using a primary culture system. Two selenium compounds were tested: selenodiglutathione (SDG), the primary metabolite of selenite, the most commonly used cancer-protective selenium compound in animal models, and the synthetic compound, 1,4-phenylenebis (methylene)selenocyanate (pXSC), one of the most potent chemopreventive selenium compounds. Both compounds induced apoptosis in the cells tested and this was associated with a strong induction of Fas ligand (Fasl). Blocking Fas activation resulted in inhibition of apoptosis. Activities of stress kinases INK (c-jun N-terminal kinase) and p38 were also induced on selenium treatment and intervention studies using specific chemical inhibitors and/or dominant negative mutants suggested that INK, but not p38, was functionally important for the induction of apoptosis and Fasl. The relative levels of induction of INK activity and Fasl also correlated with the extent of apoptosis observed. On treatment with SDG, but not pXSC, SCCs were found to preferentially activate the JNK/Fasl pathway compared to NOMCs and this correlated with enhanced sensitivity of SCCs to SDG-induced apoptosis. Both SDG and pXSC also appeared to modulate activities of other signalling proteins like extracellular regulated kinases (ERKs) 1,2 & 5 and Akt. However, functional interference with these pathways using specific chemical inhibitors or constitutively activated mutants revealed either none or a small effect on apoptosis-induction. One exception was the activation of Akt by SDG in SCCs: inhibiting its activity sensitised the cells to apoptosis significantly. Finally, preliminary xenograft studies have confirmed the induction of apoptosis in vivo, using chemopreventive dietary levels of selenium.
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