BARC: A Novel Apoptosis Regulator
Annual summary rept. 1 Jun 1999-31 May 2005
BURNHAM INST LA JOLLA CA
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Breast cancers arise due to an imbalance in cell production relative to cell turnover, resulting in a net accumulation of abnormal cells. Cell turnover is normally achieved in the body by a process known as apoptosis. Defects in apoptosis mechanisms commonly occur in breast cancers and other types of malignancies, making tumor cells difficult to kill by chemotherapy, hormonal therapy, and radiation. Restoring function of cell death pathways is a strategy for improving treatment of breast cancer. This project focused on two anti-apoptotic proteins discovered by our laboratory, BI-1 and BI-2 also known as BAR. The findings provided insights into the mechanism by which these proteins protect cancer cells from specific types of death stimuli. We demonstrated that interfering with expression or function of BI-2 BAR restores sensitivity of tumor cells to the killing mechanisms employed by immune cells, such as activators of the TNF-family receptor member Fas CD95. We found that BI-1 protects cells from endoplasmic reticulum ER stress induced apoptosis. BI-1 and anti-apoptotic Bcl-2-family protein, regulate ER calcium. Our work revealed structural elements in Bcl-2 and other ER proteins that interact with Bcl-2 to regulate ER calcium. Green tea compounds that inhibit Bcl-2 restore ER calcium. These findings provide new insights into cell death regulation in breast cancer.
- Medicine and Medical Research