Abstract

Regulation of expression of the tissue inhibitors of metalloproteinases (TIMPs) is proposed to play a seminal role in the prevention of tumor cell spreading and metastasis. The major focus of this grant application is to characterize the signal transduction pathway regulating TIMP-1 expression in human prostate cancer. In preliminary studies, we have (a) identified a novel cis-acting enhancer element HTE-1, and a putative silencer element, HTE-2, located upstream of the 5' promoter of the TIMP-1 gene; (b) identified an IL-10 responsive novel signal transacting factor (STAT7) that is phosphorylated and transported to nucleus where it binds the HTE-1 element to activate TIMP-1 expression; (c) cloned the STAT7 gene and raised monoclonal antibodies against 3 different STAT7 peptides; (d) demonstrated that STAT7 is expressed in stably transfected PC-3 ML cells and 2 x N.I. PC-3 cells; (e) found both TIMP-1 and STAT7 are associated with low grade human prostate cancer. Since IL-10 activation of STAT7 correlates with the up regulation of TIMP-1 we hypothesize that the STAT7 protein in cooperation with other signal transduction factors might be critical in up regulating TIMP-1 expression in vitro and in vivo to block tumor cell metastasis.
The specific aims of this grant application are:
Aim 1 : Characterize cooperative interactions of positive and negative transcriptional regulatory elements (i.e., HTE-1 and HTE-2) of the human TIMP-1 promoter.
Aim 2 : Study the role of the IL-10 receptor (IL-10R) signal transduction pathway in the regulation of TIMP-1 expression in human prostatic tumor cells.
Aim 3 : Evaluate the influence of IL-10 on growth, invasion, metastasis and tumor angiogenesis utilizing rSTAT7 gene transfected PC-3 cells.
Aim 4 : Evaluate STAT7 and TIMP-1 co-expression in human prostate cancer. In sum, the overall purpose of this grant application is two-fold: to assess whether an IL-10 responsive STAT7 protein can account for up regulation of TIMP-1 via binding to a unique enhancer element of the human TIMP-1 promoter; and to determine the potential importance of STAT7 expression in the tumorigenesis of prostate cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076639-04
Application #
6124461
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Mohla, Suresh
Project Start
1997-12-19
Project End
2002-11-30
Budget Start
2000-03-06
Budget End
2000-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$303,745
Indirect Cost

  Institution

Name
Mcp Hahnemann University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19102

  Publications

Wang, Min; Hu, Youji; Amatangelo, Michael D et al. (2011) Role of ribosomal protein RPS2 in controlling let-7a expression in human prostate cancer. Mol Cancer Res 9:36-50
Stearns, Mark E; Wang, Min (2011) Synergistic Effects of the Green Tea Extract Epigallocatechin-3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors. Transl Oncol 4:147-56
Stearns, Mark E; Amatangelo, Michael D; Varma, Devika et al. (2010) Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: inhibition of metastatic tumor growth in severe combined immunodeficiency mice. Am J Pathol 177:3169-79
Goodyear, S M; Amatangelo, M D; Stearns, M E (2009) Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense. Prostate 69:689-98
Dolloff, Nathan G; Shulby, Shannon S; Nelson, Autumn V et al. (2005) Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha platelet-derived growth factor receptor. Oncogene 24:6848-54
Stearns, Mark; Tran, Jordan; Francis, Mary Kay et al. (2005) Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells. Cancer Res 65:2085-8
Shulby, Shannon A; Dolloff, Nathan G; Stearns, Mark E et al. (2004) CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells. Cancer Res 64:4693-8
Stearns, Mark E; Wang, M; Hu, Youji et al. (2003) Interleukin-10 activation of the interleukin-10E1 pathway and tissue inhibitor of metalloproteinase-1 expression is enhanced by proteasome inhibitors in primary prostate tumor lines. Mol Cancer Res 1:631-42
Wang, M; Hu, Y; Stearns, M E (2003) A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells. Br J Cancer 88:1605-14
Aoyagi, K; Shima, I; Wang, M et al. (1998) Specific transcription factors prognostic for prostate cancer progression. Clin Cancer Res 4:2153-60

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