Prostate cancer is the most commonly diagnosed malignancy in American men and is the second leading cause of cancer death among men. Androgen deprivation or antiandrogen therapy has been the frontline treatment against metastatic hormone-dependent prostate cancer. Unfortunately, androgen-independent cells almost always aggressively emerge after one to three years of androgen ablation therapy. The mechanisms by which cell cycle is controlled by androgen in prostate cancer cells, as well as the mechanisms by which androgen-dependent tumor cells escape androgenic control of cell cycle are poorly understood. Thus there is a need for a more thorough understanding of these mechanisms, as well as for innovative non-endocrine strategies to halt proliferation of hormone-independent cancer cells. We have developed a unique laboratory model of human prostate cancer progression based on the androgen-dependent human prostate cancer cell line LNCaP. We have observed that androgen-dependent LNCaP 104-S tumor cells undergo a specific G1 arrest after androgen withdrawal. Conversely, androgen-independent LNCaP 104-R1/l04-R2 cells, which are cells derived from the clonal LNCaP 104-S cell line after long-term androgen deprivation, undergo G1 arrest after androgen treatment. We have now generated fully androgen-insensitive 104-IS cells from 104-S cells by serial treatment with the antiandrogen Casodex followed by androgen. 104-IS cells may represent the final stage of the clinical progression to hormone-refractory growth. We have identified Cdk2 as the most androgen-sensitive cyclin-dependent kinase in 104-S, 104-R1 and 104-R2 cells. We have also identified the cdk inhibitor p27kip1 as a factor that is partly responsible for androgen-induced G1 arrest in 104R1 and 104-R2 cells. In the first aim of this proposal we seek to identify other components of the signaling pathway starting from androgen receptor activation and terminating at either cell cycle progression or cell cycle arrest. In the second aim we seek to determine how this signaling pathway is disrupted or bypassed in androgen-insensitive cells. In the third aim we wish to explore the use of a sterol antagonist of nuclear receptors that regulate lipid homeostasis to induce apoptosis in androgen-dependent and independent prostate cancer cells. In the fourth aim we wish to explore the use of the green tea catechin epigallocatechin gallate as an adjuvant drug in combination with androgen or antiandrogen to repress prostate tumor growth and progression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Johnson, Ronald L
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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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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