Prostate cancer will be diagnosed in over 300,000 American men in 1996 and over 40,000 men will die from the disease this year, making it the second leading cause of cancer death in men. Male hormone-dependent prostate cancer which has spread outside the prostate is initially well-controlled by anti-androgen therapies, but tumor cells almost lose hormonal dependency after one to three years of treatment as cells progress to hormone-independent and metastatic stages. Unfortunately, relatively slow-growing prostate tumor cells are resistant to standard chemotherapeutic agents, making hormone- independent metastatic prostate cancer an almost uniformly fatal disease. Understanding the mechanism(s) by which hormonally- sensitive tumor cells lose dependency or otherwise acquire the ability to defeat hormone deprivation-based therapies is therefore an important objective in this study. Another objective is to investigate the use of green tea catechins and related compounds as new chemotherapeutic agents which will be effective against hormone- independent disease.
The specific aims of this study are the following: 1) To understand at the molecular level the mechanism(s) driving the transition of clonal androgen-dependent LNCaP 104-S prostate tumors cells to androgen-independent LNCaP 104-R2 cells during long-term androgen deprivation. 2) To understand at the molecular level the mechanisms involved in androgen repression of proliferation in LNCaP 104-R1 and 104-R2 cells. In addition, we wish to understand at the molecular level how LNCaP 104-R2 cells re-acquire proliferative sensitivity after re-exposure to androgen. 3) To determine whether a mutant form of the tumor suppressor p53 affects the rate at which LNCaP 104-S cells progress to androgen independence. Can expression of dominant-negative p53, through the generation of genetic instability or through some other mechanism, accelerate the rate at which androgen-independent cells appear during androgen deprivation? 4) To explore the use of green tea catechins and related compounds as anti-tumor agents against prostate cancer using the LNCaP 104-S and 104-R model of androgen-dependent and -independent prostate tumors grown in athymic mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA058073-09
Application #
6171920
Study Section
Special Emphasis Panel (ZRG2-PTHB (01))
Program Officer
Johnson, Ronald L
Project Start
1992-09-30
Project End
2002-03-31
Budget Start
2000-06-01
Budget End
2002-03-31
Support Year
9
Fiscal Year
2000
Total Cost
$234,015
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kokontis, John M; Lin, Hui-Ping; Jiang, Shih Sheng et al. (2014) Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2. PLoS One 9:e109170
Chuu, Chih-Pin; Lin, Hui-Ping; Ciaccio, Mark F et al. (2012) Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks. Cancer Prev Res (Phila) 5:788-97
Chuu, Chih-Pin; Kokontis, John M; Hiipakka, Richard A et al. (2011) Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc. Cancer Sci 102:2022-8
Peng, Lu; Hiipakka, Richard A; Xie, Jing-Tian et al. (2011) The effect of diet on the response of low-density lipoprotein receptor knockout mice to the liver X receptor agonist T1317. J Cardiovasc Pharmacol 58:102-10
Peng, Dacheng; Hiipakka, Richard A; Xie, Jing-Tian et al. (2011) A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR(-/-) mice. Br J Pharmacol 162:1792-804
Guo, Jian; Peng, Dacheng; Dai, Qing et al. (2010) Quantitative analysis of 3alpha,6alpha,24-trihydroxy-24,24-di(trifluoromethyl)-5beta-cholane, a potent synthetic steroidal liver X receptor agonist in plasma using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:1885-8
Peng, Dacheng; Hiipakka, Richard A; Xie, Jing-Tian et al. (2010) Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice. Atherosclerosis 208:126-33
Tang, Fangming; Kokontis, John; Lin, Yuting et al. (2009) Androgen via p21 inhibits tumor necrosis factor alpha-induced JNK activation and apoptosis. J Biol Chem 284:32353-8
Chuu, Chih-Pin; Chen, Rou-Yu; Kokontis, John M et al. (2009) Suppression of androgen receptor signaling and prostate specific antigen expression by (-)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett 275:86-92
Peng, Dacheng; Hiipakka, Richard A; Reardon, Catherine A et al. (2009) Differential anti-atherosclerotic effects in the innominate artery and aortic sinus by the liver X receptor agonist T0901317. Atherosclerosis 203:59-66

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