Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and is the third leading cause of cancer death in American men. As such it remains a major public health problem in the US despite improvements in diagnosis and treatment. The role of androgen receptor (AR) signaling in recurrent PCa cell growth is the subject of continuing research. It has been recognized for many years that androgen, by binding to and activating AR, promotes early stage PCa cell survival and growth. This has been the basis for androgen ablation therapy, which has served as a front-line therapy for metastatic PCa. Unfortunately, the effectiveness of androgen ablation therapy is short-lived as recurrent hormone-independent PCa cells usually emerge after one to three years of treatment. Our laboratory has also identified a repressive function of androgen in PCa cells when AR is expressed at high level. We hypothesize that this repression function of AR may be a remnant of AR action in normal healthy prostate epithelial cells and that restoring this repression function by over-expression may be effective therapy in many PCa patients. In the first aim we propose to test this hypothesis in preclinical "proof of concept" experiments by generating adenoviral constructs expressing the AR gene and use them to infect a wide array of prostate tumor cells in vitro cell culture and in vivo as tumor xenografts in athymic mice. In the second aim, will explore the mechanistic basis for androgenic repression of growth and induction of apoptosis to provide a rationale for AR replacement therapy. In the third aim we will examine novel signaling pathways that may drive cell proliferation in androgen-independent cells. We recently uncovered three regulators in a screen for differentially expressed genes in androgen-dependent vs. androgen-independent PCa cells that we hypothesize cooperate to confer androgen-independent growth. In the fourth aim, we will examine liver X receptor (LXR) signaling and the regulation of cholesterol and lipid homeostasis in PCa cells as a novel means to control cell growth. We recently found that LXR agonists repress cell proliferation in both androgen-dependent and -independent PCa cells. Prostate cancer (PCa) remains a major public health problem in the US despite improvements in diagnosis and treatment. It has been recognized for many years that the male hormone androgen, by binding to and activating androgen receptor (AR), promotes early stage PCa cell survival and growth. However, our laboratory has also identified a repressive function of androgen when AR is expressed at high level. We propose to test whether enforced over-expression of AR can effectively repress prostate cancer growth in laboratory models, to determine the mechanisms of how androgen represses tumor growth and how hormone-independent cells grow, and lastly, to examine the feasibility of using liver X receptor agonists to modulate prostate tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA058073-19
Application #
8206835
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Johnson, Ronald L
Project Start
1992-09-30
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
19
Fiscal Year
2012
Total Cost
$305,713
Indirect Cost
$106,552
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
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; 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, 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
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. (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
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
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; Dai, Qing et al. (2008) Antiatherosclerotic effects of a novel synthetic tissue-selective steroidal liver X receptor agonist in low-density lipoprotein receptor-deficient mice. J Pharmacol Exp Ther 327:332-42
Chuu, Chih-Pin; Chen, Rou-Yu; Hiipakka, Richard A et al. (2007) The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells. Biochem Biophys Res Commun 357:341-6
Chuu, Chih-Pin; Kokontis, John M; Hiipakka, Richard A et al. (2007) Modulation of liver X receptor signaling as novel therapy for prostate cancer. J Biomed Sci 14:543-53

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