Cell-to Cell interactions are known to play a critical role in morphogenesis and pathogenesis of the prostate gland. Neuroendocrine (NE) cells secrete numerous peptide hormones which induce mitogenesis in proliferation-competent cells. Recent studies by the PI suggest that primary human prostate epithelial cells secrete immunoreactive calcitonin (CT-I) in culture, and its secretion from prostate carcinoma (PC)-derived cells is several-fold greater than that from the cells-derived from benign prostatic hypertrophy(BPH). In situ hybridization and immunohistochemistry studies of tumors have shown that 1) CT mRNA, CT-I and CT-R mRNA are localized in the basal layer of benign prostate gland. In contrast, CT mRNA, CT-I, CT-R mRNA and CT binding sites are localized in luminal layers of malignant prostate epithelium, and their expression increases with tumor progression. Poorly differentiated PC-3M cells and undifferentiated NRP-152 cells co-express CT and CT-R mRNAs and well-differentiated LnCaP cells express only CT-R. Exogenously added CT stimulates DNA synthesis of primary PC cells, LnCaP and PC-3M cells; and anti-sCT inhibits this growth. CT also inhibited TGF-b and TGF-b receptor immunoreactivity in prostate cells. Considered with the role of TGF-b in cell differentiation and apoptosis, it is conceivable that CT promotes tumor progression by arresting differentiation, and increasing the growth of transformed cells.
Specific Aim 1 will test the effect of manipulation of CT and CT-R expression on proliferative, invasive and tumorigenic activities of prostate cancer cells.
Specific Aim 2 will delineate mitogenic signaling pathway activated by CT in these cells.
Specific Aim 3 will examine the effect of CT on transdifferentiation and TGF-b expression in these cell lines. The proposed studies will define the role for prostatic CT in regulation of growth and differentiation in malignant human prostate gland.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096534-02
Application #
6522953
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O1))
Program Officer
Mohla, Suresh
Project Start
2001-09-26
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$185,000
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Aljameeli, Ahmed; Thakkar, Arvind; Shah, Girish (2017) Calcitonin receptor increases invasion of prostate cancer cells by recruiting zonula occludens-1 and promoting PKA-mediated TJ disassembly. Cell Signal 36:1-13
Aljameeli, Ahmed; Thakkar, Arvind; Thomas, Shibu et al. (2016) Calcitonin Receptor-Zonula Occludens-1 Interaction Is Critical for Calcitonin-Stimulated Prostate Cancer Metastasis. PLoS One 11:e0150090
Thakkar, Arvind; Aljameeli, Ahmed; Thomas, Shibu et al. (2016) A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells. Endocr Relat Cancer 23:1-14
Alzghoul, Salah; Hailat, Mohammad; Zivanovic, Sandra et al. (2016) Measurement of serum prostate cancer markers using a nanopore thin film based optofluidic chip. Biosens Bioelectron 77:491-8
Thakkar, Arvind; Bijnsdorp, Irene V; Geldof, Albert A et al. (2013) Profiling of the calcitonin-calcitonin receptor axis in primary prostate cancer: clinical implications and molecular correlates. Oncol Rep 30:1265-74
Mudit, Mudit; Khanfar, Mohammad; Shah, Girish V et al. (2011) Methods for evaluation of structural and biological properties of antiinvasive natural products. Methods Mol Biol 716:55-71
Liang, Yuanyuan; Ankerst, Donna P; Ketchum, Norma S et al. (2011) Prospective evaluation of operating characteristics of prostate cancer detection biomarkers. J Urol 185:104-10
Mudit, Mudit; Khanfar, Mohammad; Muralidharan, Anbalagan et al. (2009) Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products. Bioorg Med Chem 17:1731-8
Shah, Girish V; Muralidharan, Anbalagan; Gokulgandhi, Mitan et al. (2009) Cadherin switching and activation of beta-catenin signaling underlie proinvasive actions of calcitonin-calcitonin receptor axis in prostate cancer. J Biol Chem 284:1018-30
Shah, Girish V; Muralidharan, Anbalagan; Thomas, Shibu et al. (2009) Identification of a small molecule class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis. Mol Cancer Ther 8:509-20

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