BCL-2 INHIBITS THE APOPTOTIC PATHWAY INDUCED BY VITAMIN E SUCCINATE IN THE SK-BR-3 HUMAN BREAST CANCER CELL LINE

Abstract

In recent years, one of the areas of intense interest in cancer research has been the use of naturally occurring compounds as chemotherapeutic agents. Our laboratory, along with others, has been studying the efficacy of vitamin E succinate (VES), a derivative of vitamin E, to inhibit the growth of human breast cancer cells. Previously, our laboratory had shown that VES caused apoptosis, programmed cell death, in certain breast cancer cell lines, in particular the estrogen receptor-negative SK-BR-3 cell line. VES-induced apoptosis in this cell line was mediated by Fas, a member of the tumor necrosis factor receptor-I (TNF-R1) family of death receptors. There are two known pathways for Fas to cause apoptosis using a family of proteases, the caspases, which can be either dependent or independent of changes to the mitochondria. In this study, the intracellular pathway in SK-BR-3 cells by which VES mediates apoptosis through Fas was examined. VESinduced apoptosis mediated by Fas occurs through altering the function of the mitochondria by demonstrating the cleavage of key proteins: Bid, caspase-9 and caspase- 3, and the release of cytochrome C from the mitochondria. This apoptosis is blocked by overexpression of Bc1-2, a known anti-apoptotic protein. The induction of apoptosis in an estrogen receptor-negative cell line by VES is significant because estrogen receptornegative breast tumors have been found to be more invasive tumors, resistant to conventional anti-estrogen therapies, and negative for Bc1-2 expression. The ability of VES to kill these cells presents a new approach to therapy for the more aggressive breast tumors.