Abstract

) Prostate cancer has become the most common cancer affecting men in this country. Androgen has been proposed to be a risk factor promoting the progression of prostate epithiums from latent carcinomas to invasive cancers. Androgen stimulation of prostate cancer cell growth is associated with a decrease in cellular prostatic acid phosphatase (PAcP) activity, the major protein tyrosine phosphatase in the cells. The expression of a putative cellular form of PAcP driven by a complement dioxyribonucleic acid (cDNA) expression vector correlates with a diminished growth rate. The regulation of tyrosine phosphorylation is an important process in cell proliferation, we therefore propose that androgen-responsive cellular PAcP ultimately plays an important role in cell growth regulation of prostate epitheliums and be involved in cancer progression. The approach in this proposal is to delineate the regulatory mechanism of phosphotyrosine (p-tyr) dephosphorylation by cellular PAcP. The working hypothesis is that the understanding of p-tyr dephosphorylation by androgen- responsive PAcP will lead us to understand one mechanism of androgen effects in the multistage prostate malignant transformation. In order to test this working hypothesis directly, the following specific aims will be accomplished. We will transfect several different cells with a PAcP cDNA expression vector to examine the cell growth regulation possibly by cellular PAcP expression. Cell growth regulation by PAcP will be further studied by transfecting cells with PAcP cDNA in an inducible expression vector and compare the biological effects of PAcP expression in the presence or absence of inducing agents. The mechanism of PAcP regulation on the cellular growth will be investigated by identifying its putative substrate phosphoprotein(s) that has a decreased p-tyr level in PAcP- expressing cells. The effect of cellular PAcP expression on the tumor development in nude mice will be examined by injecting PAcP cDNA- transfected cells subcutaneously. The results from these proposal experiments will lead to our long term goal in understanding the mechanisms of multistage prostate malignant transformation for improving the prevention and the therapy of the disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072274-03
Application #
2700710
Study Section
Special Emphasis Panel (SRC (28))
Program Officer
Liu, Yung-Pin
Project Start
1996-07-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Nebraska Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198

  Publications

Zhang, Xiu-Qing; Kondrikov, Dmitry; Yuan, Ta-Chun et al. (2003) Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene 22:6704-16
Igawa, Tsukasa; Lin, Fen-Fen; Rao, Prathibha et al. (2003) Suppression of LNCaP prostate cancer xenograft tumors by a prostate-specific protein tyrosine phosphatase, prostatic acid phosphatase. Prostate 55:247-58
Igawa, Tsukasa; Lin, Fen-Fen; Lee, Ming-Shyue et al. (2002) Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 50:222-35
Lin, M F; Lee, M S; Zhou, X W et al. (2001) Decreased expression of cellular prostatic acid phosphatase increases tumorigenicity of human prostate cancer cells. J Urol 166:1943-50
Zelivianski, S; Verni, M; Moore, C et al. (2001) Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta 1539:28-43
Zhang, X Q; Lee, M S; Zelivianski, S et al. (2001) Characterization of a prostate-specific tyrosine phosphatase by mutagenesis and expression in human prostate cancer cells. J Biol Chem 276:2544-50
Karan, D; Johansson, S L; Lin, M F et al. (2001) Expression of tumor-associated glycoprotein-72 (TAG-72) antigen in human prostatic adenocarcinomas. Oncol Rep 8:1123-6
Lin, M F; Zhang, X Q; Dean, J et al. (2001) Protein kinase C pathway is involved in regulating the secretion of prostatic acid phosphatase in human prostate cancer cells. Cell Biol Int 25:1139-48
Zelivianski, S; Larson, C; Seberger, J et al. (2000) Expression of human prostatic acid phosphatase gene is regulated by upstream negative and positive elements. Biochim Biophys Acta 1491:123-32
Lin, M F; Lee, M S; Garcia-Arenas, R et al. (2000) Differential responsiveness of prostatic acid phosphatase and prostate-specific antigen mRNA to androgen in prostate cancer cells. Cell Biol Int 24:681-9

Showing the most recent 10 out of 17 publications