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The Physiological Function of Store-Operated Ca 2+ Entry in Prostate Cancer Cells

by
Na Li
B.S., 1998
Henan Medical University
People`s Republic of China

Thesis Advisor: Jianjie Ma, PhD
Graduate Program of Physiology and Integrative Biology

CABM 010

Thursday, March 20, 2008
1:00 pm


Abstract

Recent studies have shown that the acquired apoptosis-resistant nature of androgen-independent prostate cancer is associated with reduced function of store-operated Ca 2+ entry (SOCE). This study investigates the functional interaction between Bax and SOCE during apoptosis signaling cascade in prostate cancer. Our previous findings showed that NRP-154, an androgen-independent prostate cancer cell line, could sustain overexpression of exogenous Bax without undergoing apoptosis. Here we show that sustained overexpression of Bax in NRP-154 cells leads to down regulation of SOCE and reduced Ca 2+ storage inside the endoplasmic reticulum (ER). While reduced SOCE may represent an adaptive mechanism for cell survival, increased levels of Bax in the latent state enhanced the sensitivity of NRP-154 cells to TGF-b and thapsigargin (TG)-induced apoptosis. This enhanced apoptosis could be reduced by 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of SOCE, or reversed under conditions where SOCE was only partially activated. Our results demonstrate a functional interaction between Bax and SOCE in apoptosis of prostate cancer, and support the concept that improving this interaction has therapeutic implications for prostate cancer.
Full length Bax (p21Bax) is cleaved into a truncated form (p18Bax) and a small amino peptide (p3Bax) by calpain during apoptosis in tumor cells. Although studies show that p18Bax behaves like a BH3 protein and can produce more toxic effects than p21Bax, little is known about the function of p3Bax. We investigated the function of p3Bax by using a membrane permeable peptide to transducer p3Bax into NRP-154 cells and found that p3Bax increased the SOCE activity and IP3 sensitive ER Ca 2+ store in NRP-154 cells. Our study is consistent with Bax’s regulatory effect on SOCE and supports the concept that p3Bax may have therapeutic potential to increase SOCE activity and assist in the treatment of prostate cancer.


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