Abstract

Transforming growth factor-b (TGF-beta) is a negative regulator of prostate growth via its ability to inhibit cell proliferation and induce apoptosis in epithelial cells. Evidence indicates that in prostate cancer an increase in epithelial TGF-beta expression is paralleled by loss of expression of its membrane receptors TbetaRI and TbetaRII. The long-term goal of the proposed studies is to identify the interplay between the androgen axis and TGF-beta signaling pathways during prostate tumorigenesis. Our recent studies demonstrated that restoration of expression of the functional TbetaRII receptor in human prostate cancer cells LNCaP that are resistant to TGF-beta, leads to TGF-beta sensitivity and suppression of tumorigenic growth via cell cycle arrest and apoptosis induction. In this proposal we will use this model of hormone-sensitive TGF-beta responsive prostate cancer cells to explore the molecular mechanism underlying the dysfunctional TGF-beta signaling pathway in prostate tumorigenesis.
In Specific Aim 1 we will determine the ability of androgens to affect the action of TGF-beta on prostate cancer cell growth as linked to deregulation of cell cycle (cdk inhibitors) and apoptosis induction (caspases, bcl-2). The effect of androgens on TGF-beta mediated suppression of in vivo tumorigenic growth of LNCaP TbetaRII cells will be determined using orthotopic injections.
In Specific Aim 2 using transfections and co-immunoprecipitation approaches we will investigate the functional involvement of the Smad intracellular effectors of TGF-beta in transducing the apoptotic signals to the nucleus.
In Specific Aim 3 the interaction between the androgen receptor (AR) and TGF-beta signaling pathways in LNCaP TbetaRII prostate cells will be characterized using immunoprecipitation assays. These studies will establish: a) that androgens contribute to the impairment of TGF-beta signaling in prostate cancer cells; and b) the significance of defects in post-receptor intracellular mediators of TGF-beta signal, the Smads, in the development of hormone-resistance in prostate cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053525-05
Application #
6657314
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Mullins, Christopher V
Project Start
1997-09-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$199,777
Indirect Cost

  Institution

Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Zhu, Haining; Zhao, Jun; Zhu, Beibei et al. (2012) EMMPRIN regulates cytoskeleton reorganization and cell adhesion in prostate cancer. Prostate 72:72-81
Zhu, Brian; Zhai, Jianjun; Zhu, Haining et al. (2010) Prohibitin regulates TGF-beta induced apoptosis as a downstream effector of Smad-dependent and -independent signaling. Prostate 70:17-26
Pu, Hong; Collazo, Joanne; Jones, Elisabeth et al. (2009) Dysfunctional transforming growth factor-beta receptor II accelerates prostate tumorigenesis in the TRAMP mouse model. Cancer Res 69:7366-74
Zhu, Meng-Lei; Kyprianou, Natasha (2008) Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 15:841-9
Schwarze, Steven R; Lin, Eric W; Christian, Perry A et al. (2008) Intracellular death platform steps-in: targeting prostate tumors via endoplasmic reticulum (ER) apoptosis. Prostate 68:1615-23
Zhu, Meng-Lei; Partin, James V; Bruckheimer, Elizabeth M et al. (2008) TGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells. Prostate 68:287-95
Zhu, Beibei; Fukada, Kei; Zhu, Haining et al. (2006) Prohibitin and cofilin are intracellular effectors of transforming growth factor beta signaling in human prostate cancer cells. Cancer Res 66:8640-7
Reynolds, Arich Ryan; Kyprianou, Natasha (2006) Growth factor signalling in prostatic growth: significance in tumour development and therapeutic targeting. Br J Pharmacol 147 Suppl 2:S144-52
McKenzie, Shaun; Kyprianou, Natasha (2006) Apoptosis evasion: the role of survival pathways in prostate cancer progression and therapeutic resistance. J Cell Biochem 97:18-32
Zeng, L; Kyprianou, N (2005) Apoptotic regulators in prostatic intraepithelial neoplasia (PIN): value in prostate cancer detection and prevention. Prostate Cancer Prostatic Dis 8:7-13

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