Transforming growth factor-betas (TGF-betas) are 25 kDa multifunctional autocrine/paracrine peptides with potent activity on growth suppression and apoptosis of epithelial cells. In the prostate, expression of TGF-beta protein and their receptors are induced upon androgen ablation, coincident with apoptotic cell death that occurs concomitantly in this tissue. Prostatic cells lose dependence on androgens and become resistant to TGF-beta responses during carcinogenesis, through mechanisms that remain to be defined. Further support for a tumor suppressor role of TGF-beta in the prostate comes from studies where we ablated TGF-beta signaling in two non-tumorigenic cell lines (NRP-152 and DP-153) by retroviral transduction of a dominant-negative TbetaRII, and showed the consequent loss of response to TGF-beta triggers malignant transformation. Loss of TGF-beta receptor expression is one of many potential mechanisms of TGF-beta resistance. Other pathways may involve activation of certain oncogenes that intercept TGF-beta signals at various levels. We have recently reported that DHT can directly block TGF-beta signaling through an association between AR and Smad3, leading to the transcriptional inactivation of Smad3 in LNCaP and NRP-154 prostatic epithelial cells. We provide evidence using EMSAs that AR's inhibitory effect is through blocking the binding of Smad3 to Smad Binding Elements (SBE) of target genes. Here we propose to investigate:1) the effects of DHT/AR on growth arrest and apoptosis induced by TGF-beta (or active Smad3), 2) expression of TGF-beta inducible genes by DHT/AR, 3) the structure/functional basis behind the binding of AR to Smad3, 4) possible function of AR co-activators as co-regulators or Smad3 through AR, and 5) differences in the interaction of AR with Smad3 in various nontumorigenic and tumorigenic cell lines. We believe these studies will most certainly impact on the therapeutic intervention of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102074-05
Application #
7345468
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2004-03-02
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2010-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$293,511
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Shankar, Eswar; Song, Kyung; Corum, Sarah L et al. (2016) A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells. J Biol Chem 291:5512-26
Lambertz, Irina; Kumps, Candy; Claeys, Shana et al. (2015) Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment. Clin Cancer Res 21:3327-39
Wahdan-Alaswad, Reema S; Bane, Kara L; Song, Kyung et al. (2012) Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin. Mol Cancer Res 10:821-33
Shola, D T N; Wang, H; Wahdan-Alaswad, R et al. (2012) Hic-5 controls BMP4 responses in prostate cancer cells through interacting with Smads 1, 5 and 8. Oncogene 31:2480-90
Wahdan-Alaswad, Reema S; Song, Kyung; Krebs, Tracy L et al. (2010) Insulin-like growth factor I suppresses bone morphogenetic protein signaling in prostate cancer cells by activating mTOR signaling. Cancer Res 70:9106-17
Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2010) DHT selectively reverses Smad3-mediated/TGF-beta-induced responses through transcriptional down-regulation of Smad3 in prostate epithelial cells. Mol Endocrinol 24:2019-29
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Yang, Jiayi; Wahdan-Alaswad, Reema; Danielpour, David (2009) Critical role of Smad2 in tumor suppression and transforming growth factor-beta-induced apoptosis of prostate epithelial cells. Cancer Res 69:2185-90
Yang, J; Song, K; Krebs, T L et al. (2008) Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression. Oncogene 27:5326-38
Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2008) Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II. Cancer Res 68:8173-82

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