Role of Clusterin Deprivation-Mediated Cell Death in Breast Cancer Cells

摘要

During the two years period, we demonstrated that human CLU gene produced at least two forms of CLU protein, secretory CLU and nuclear CLU that were made via alternative splicing mechanism. In the nCLU mRNA exon II that contains endoplasmic reticulum targeting sequence is spliced out resulting in a protein that remains in the cell and enters the nucleus after apoptotic signal. Inhibition of nCLU protein by sRNA in breast cancer cells resulted in higher resistance to ionizing radiation, suggesting that nCLU is a pro-apoptotic protein. Inhibition of sCLU resulted in higher radiosensitivity, indicating that sCLU is anti-apoptotic. Breast cancer cell line that lack estrogen receptor (ER) (T47D: C4:2W) had higher levels of nCLU than its ER-positive isogenic counterpart (T47D:A18) and was significantly more sensitive to IR. The effect of nCLU vs sCLU inhibition in breast cancer cell on their response to tamoxifen/ estrogen ablation is currently under investigation. We are also studying human CLU promoter for the elements responsible for its activation by estrogen deprivation.