Store-operated Ca channels control homeostasis between extracellular Ca reservoir and intracellular Ca storage, and play important roles in the signaling cascade of apoptosis in a wide variety of cells including prostate epithelia. Recent studies have shown that the acquired apoptosis-resistant nature of androgen- independent prostate cancer is associated with reduced function of store-operated Ca entry (SOCE), but the physiological function of SOCE in the initiation and amplification of apoptosis in prostate cancer remains largely unknown. Toward understanding the regulatory function of SOCE in apoptosis, we have identified a novel 8 kDa cytosolic protein (P8soc) that appears to be an integral component of SOCE. In addition, we have a tumorigenic prostatic epithelial cell line (NRP-154) that undergoes apoptosis in response to activation of SOCE, but surprisingly these cells can resist high level of exogenous Bax without undergoing apoptosis. This unique property enables us to explore the synergistic interaction between Bax and SOCE in apoptosis of prostate cancer. Using NRP-154 cells, we found that a 22 amino acid presenilin loop peptide (PLP), an intermediate apoptosis byproduct, can alter intracellular Ca release and amplify the signaling cascade of apoptosis. Extending the above preliminary studies, the current project will be centered on testing the hypothesis that SOCE contributes to the growth and death of cells by detecting a balanced retrograde signal from endoplasmic reticulum (ER) to the cytosol and the plasma membrane. Coordinated feed-back and feed- forward control mechanisms involving the interaction of apoptotic co-factors with SOCE play a key role in the execution and amplification of apoptosis in prostate cancer. Through understanding the retrograde signaling from calreticulin in the ER to PSsoc in the cytosol, we hope to establish the functional correlation between graded-activation of SOCE and synergistic interaction between Ca and Bax in the initiation of apoptosis (Aim 1). By elucidating the molecular interactions among PSsoc, PLP and other intermediate byproducts of apoptosis, we aim to establish the regulatory mechanisms of intracellular Ca release and extracellular Ca entry in the execution steps of apoptosis in prostate cancer (Aim 2). Knowledge on the molecular interactions between apoptosis mediators and cytosolic factors that control SOCE will enable us to establish therapeutic agents that target Ca signaling in cancer and degenerative diseases. ? ?
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