This proposal is designed to investigate the hypothesis that vitamin E succinate (VES) causes tumor cell death by induction of apoptosis via the dual action of increasing negative growth factor (TGF-( ) signaling pathway and enhancing stress response signaling pathway (SAPKs/JNKs) which coverage on AP-1 transcription factors, leading to either repression of genes necessary for survival or stimulation of genes associated with suicide function. Initial studies indicated that VES induced greater than 70 percent of cultured human breast cancer cells (MCF-7 and MDA-MB-435) to undergo apoptosis after 4 days of treatment. Support for the dual signaling pathways comes from indirect evidence showing increased ERK and JNK activities in VES-treated cells. Exposure to VES was also found to induce prolonged elevation of c-jun mRNA and protein. This was accompanied by increased nuclear protein binding to AP-1 and to CRE consensus sequences as well as increased transactivation activity as monitored by AP-1 dependent reporter gene expression.
The specific aims of the proposal are (1) to determine the contribution of AP-1 constituents to VES-induced apoptosis in human breast cancer cells, and (2) to characterize the contributions of JNK and ERK to VES-induced apoptosis. The models for the research will include both the estrogen-responsive MCG-7 cells, as well as the estrogen- unresponsive MDA-MB-435 cells. Cells that are stably or transiently transfected with a variety of gene constructs will also be employed in various aspects of the proposed studies.
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