Aberrant regulation of growth of the human prostate is responsible for much of the morbidity and mortality associated with BPH and other forms of prostatic neoplasia in the aging adult male population. In part, growth of the prostate is mediated by the paracrine/autocrine interaction between NGF and its cognate high affinity TrkA receptor and the low affinity NGF receptor (LNGFR). Hence, based upon our prior published work in conjunction with additional preliminary studies reported herein, we propose to test the hypothesis that the two types of NGF receptors, TrkA and the LNGFR stimulate and inhibit growth, respectively, in human prostate epithelial cells. Studies to support this hypothesis are proposed as three specific aims. The first specific aim is to characterize expression of the Trk family members, TrkA, TrkB and TrkC in the normal, BPH and neoplastic pathologic prostate by in situ hybridization and immunohistochemistry. Differential expression of these Trk family members will be correlated with the pathology of the prostate and a proliferating cell nuclear antigen (PCNA) proliferation index. In this manner, changes in the expression of the Trks may be related to the rate of growth and pathology of the prostate. The second specific aim will directly test the putative growth stimulatory effects of the TrkA receptor by transfection with a double stable Tet-On inducible expression system in which Doxycycline is used to regulate the level of TrkA overexpression in a prostate epithelial cell line. The induced overexpression of TrkA will be evaluated in relation to the rate of growth of these cells. The third specific aim will directly test the putative growth inhibitory effects of the LNGFR by transfection with a double stable Tet-On inducible expression system in which Doxycycline is used to regulate the level of LNGFR re-expression in a prostate epithelial cell line. The induced re-expression of the LNGFR will be evaluated for changes in the rate of growth of these cells as it pertains to proliferation and induction of programmed cell death. Our studies have already identified NGF receptors as targets for the clinical perturbation of prostate growth. As a result, phase I clinical trials are currently underway with an indolocarbazole Trk antagonist for the treatment of aberrant prostatic growth at Georgetown University Medical Center. A comprehensive investigation of the NGF receptors in the human prostate should be broadly applicable to our understanding of the mechanism of NGF mediated autocrine/paracrine regulation of prostate growth and hasten the translation of these observations to the clinical setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052626-02
Application #
6177970
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Rankin, Tracy L
Project Start
1999-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
2
Fiscal Year
2000
Total Cost
$232,254
Indirect Cost
Name
Georgetown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Wynne, Shehla; Djakiew, Daniel (2010) NSAID inhibition of prostate cancer cell migration is mediated by Nag-1 Induction via the p38 MAPK-p75(NTR) pathway. Mol Cancer Res 8:1656-64
Khwaja, Fatima S; Quann, Emily J; Pattabiraman, Nagarajan et al. (2008) Carprofen induction of p75NTR-dependent apoptosis via the p38 mitogen-activated protein kinase pathway in prostate cancer cells. Mol Cancer Ther 7:3539-45
Quann, Emily J; Khwaja, Fatima; Djakiew, Daniel (2007) The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells. Cancer Res 67:11402-10
Quann, Emily J; Khwaja, Fatima; Zavitz, Kenton H et al. (2007) The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. Cancer Res 67:3254-62
Nalbandian, Angele; Djakiew, Daniel (2006) The p75(NTR) metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells. Clin Exp Metastasis 23:107-16
Allen, Jeffrey; Khwaja, Fatima; Byers, Stephen et al. (2005) The p75NTR mediates a bifurcated signal transduction cascade through the NF kappa B and JNK pathways to inhibit cell survival. Exp Cell Res 304:69-80
Nalbandian, Angele; Pang, Alan L Y; Rennert, Owen M et al. (2005) A novel function of differentiation revealed by cDNA microarray profiling of p75NTR-regulated gene expression. Differentiation 73:385-96
Allen, Jeffrey; Khwaja, Fatima; Djakiew, Daniel (2004) Gene therapy of prostate xenograft tumors with a p75NTR lipoplex. Anticancer Res 24:2997-3003
Tabassum, Arshia; Khwaja, Fatima; Djakiew, Daniel (2003) The p75(NTR) tumor suppressor induces caspase-mediated apoptosis in bladder tumor cells. Int J Cancer 105:47-52
Khwaja, Fatima; Djakiew, Daniel (2003) Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor. Mol Carcinog 36:153-60

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