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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095739-07
Application #
7226698
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Spalholz, Barbara A
Project Start
2001-08-01
Project End
2011-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
7
Fiscal Year
2007
Total Cost
$245,631
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Physiology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Ko, Jae-Kyun; Choi, Kyoung-Han; Peng, Jun et al. (2011) Amphipathic tail-anchoring peptide and Bcl-2 homology domain-3 (BH3) peptides from Bcl-2 family proteins induce apoptosis through different mechanisms. J Biol Chem 286:9038-48
Ni, Hong-Min; Baty, Catherine J; Li, Na et al. (2010) Bid agonist regulates murine hepatocyte proliferation by controlling endoplasmic reticulum calcium homeostasis. Hepatology 52:338-48
Zhu, Michael X; Evans, A Mark; Ma, Jianjie et al. (2010) Two-pore channels for integrative Ca signaling. Commun Integr Biol 3:12-7
Li, Na; Lin, Peihui; Cai, Chuanxi et al. (2009) The amino-terminal peptide of Bax perturbs intracellular Ca2+ homeostasis to enhance apoptosis in prostate cancer cells. Am J Physiol Cell Physiol 296:C267-72
Ko, Jae-Kyun; Choi, Kyoung-Han; Pan, Zui et al. (2007) The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis. J Cell Sci 120:2912-23
Landstrom, Andrew P; Weisleder, Noah; Batalden, Karin B et al. (2007) Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol 42:1026-35
Weisleder, Noah; Brotto, Marco; Komazaki, Shinji et al. (2006) Muscle aging is associated with compromised Ca2+ spark signaling and segregated intracellular Ca2+ release. J Cell Biol 174:639-45
Zhao, Xiaoli; Weisleder, Noah; Han, Xuehai et al. (2006) Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. J Biol Chem 281:33477-86
Hirata, Yutaka; Brotto, Marco; Weisleder, Noah et al. (2006) Uncoupling store-operated Ca2+ entry and altered Ca2+ release from sarcoplasmic reticulum through silencing of junctophilin genes. Biophys J 90:4418-27
Ko, Jae-Kyun; Ma, Jianjie (2005) A rapid and efficient PCR-based mutagenesis method applicable to cell physiology study. Am J Physiol Cell Physiol 288:C1273-8

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