The neurotrophin receptor, p75 NTR, binds the neurotrophin family (e.g. NGF) of growth factors. The p75 NTR is a member of the tumor necrosis factor receptor superfamily. Specific members of this superfamily, including the p75 NTR, share similar sequence motifs designated """"""""death domains"""""""" that signal initiation of apoptotic function and inhibition of growth. The p75 NTR exhibits an inverse association of protein expression with malignant progression of the human prostate. Furthermore, we have shown that the p75 NTR is a novel tumor suppressor in human prostate cancer. This is significant since the pathologic elimination of the p75 NTR tumor suppressor facilitates growth during malignant progression of the human prostate. To further elucidate the role of the p75 NTR as a tumor suppressor in the prostate we will test the hypothesis that a functional p75 NTR in prostate cancer cells modifies post-receptor effectors that regains inhibition of growth control. The mechanisms of action of p75 NTR mediated suppression of prostate growth will be assessed in the following five specific aims.
In aim 1, we will examine p75 NTR mediated death receptor signal transduction via both the NF-kappaB/I-kappaB pathway and/or activation of the JNK pathway as it relates to inhibition of proliferation and activation of apoptosis.
In aim 2, we will demonstrate p75 NTR dependent inhibition of prostate tumor cell growth via impeded progression of the cell cycle and changes in expression/activity of the cyclin/cdk holoenzyme complexes.
In aim 3, we will examine p75 wrR mediated induction of apoptosis as it relates to changes in the expression ofpro-apoptotic (e.g. Bax) and anti-apoptotic (e.g. Bcl-xL) effectors, and activation of the downstream caspase cascade.
In aim 4 we will examine the dual role of p75 NTR as a metastasis suppressor and establish a mechanistic relationship between p75 NTR dependent suppression of metastasis and induction of apoptosis and/or reduced cell proliferation in the metastatic prostate tumor cells.
In aim 5, we will demonstrate pre-clinical gene therapy application of p75 NTR vectors by intra-tumoral injection in SCID mice. These studies should elucidate the mechanism(s) of action of the p75 NTR as a tumor and metastasis suppressor of human prostate growth, and its potential application for gene therapy of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052626-05
Application #
6761883
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Rankin, Tracy L
Project Start
1999-05-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$240,562
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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