Hormonal therapy is the most common treatment for advanced prostate cancer. However, patients usually die of an androgen-refractory form of the disease with no hope for further treatment. Our laboratory has demonstrated that disruption of the androgen receptor (AR) inhibits proliferation of androgen-refractory PCa cells. Moreover, AR can be activated by nonandrogenic factors, such as IL-6 and IGF-I. This has accentuated the need to study the molecular mechanisms underlying the activation of the AR in androgen-refractory PCa. Thus, we have focused our attention on the role of coregulators in androgen-independent activation of the AR. Studies suggest that the coactivators CBP and p300 are required for IL-6-mediated transactivation of the AR. CBP appears to act by binding to the AR; p300 appears to act by binding to STAT3, a component of the IL-6 pathway. Additionally, two core components of the human SWI/SNF complex, BAF170 and BAF60b, are overexpressed in androgen-refractory PCa cells. From these data we hypothesize that IL-6-induced transactivation of AR is mediated by the AR-STAT3 interaction bar recruitment of transcriptional coregulators. including CBP, p300 and components of the SWI/SNF complex. To test this hypothesis, we propose to (1) determine if the CBP/AR complex provides a foundation for IL-6-induced transactivation of the AR; (2) determine if the recruitment of the p300/STAT3 complex into AR is a key factor in IL-6-induced transactivation of the AR; (3) determine if the core components of the SWI/SNF complex facilitate IL-6-induced transactivation of the AR. These studies should enhance our understanding of androgen-refractory prostate cancer and may identify new therapeutic targets for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060920-04
Application #
6790023
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O1))
Program Officer
Mullins, Christopher V
Project Start
2001-09-30
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$214,500
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Heemers, Hannelore V; Debes, Jose D; Tindall, Donald J (2008) The role of the transcriptional coactivator p300 in prostate cancer progression. Adv Exp Med Biol 617:535-40
Dehm, Scott M; Tindall, Donald J (2006) Molecular regulation of androgen action in prostate cancer. J Cell Biochem 99:333-44
Dehm, Scott M; Tindall, Donald J (2006) Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. J Biol Chem 281:27882-93
Huang, Haojie; Regan, Kevin M; Lou, Zhenkun et al. (2006) CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314:294-7
Murillo, Horacio; Schmidt, Lucy J; Karter, Melissa et al. (2006) Prostate cancer cells use genetic and epigenetic mechanisms for progression to androgen independence. Genes Chromosomes Cancer 45:702-16
Mora, Gloria R; Olivier, Kenneth R; Mitchell Jr, Richard F et al. (2005) Regulation of expression of the early growth response gene-1 (EGR-1) in malignant and benign cells of the prostate. Prostate 63:198-207
Huang, Haojie; Regan, Kevin M; Wang, Fang et al. (2005) Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci U S A 102:1649-54
Debes, Jose D; Sebo, Thomas J; Heemers, Hannelore V et al. (2005) p300 modulates nuclear morphology in prostate cancer. Cancer Res 65:708-12
Debes, Jose D; Comuzzi, Barbara; Schmidt, Lucy J et al. (2005) p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6. Cancer Res 65:5965-73
Debes, Jose D; Roberts, Rosebud O; Jacobson, Debra J et al. (2004) Inverse association between prostate cancer and the use of calcium channel blockers. Cancer Epidemiol Biomarkers Prev 13:255-9

Showing the most recent 10 out of 20 publications