Mechanisms and Control of the Functions of Nuclear Receptors for Male Hormones and other Hormones Involved in Progression of Prostate Cancer as well as Cardiovascular and Cerebrovascular Diseases
My laboratory is investigating molecular mechanisms involved in the control of androgen action and how androgen signaling is related to development and progression of prostate cancer. We are also investigating the effects of dietary agents on endocrine responses including the effects of green tea catechins on endocrine systems, fat metabolism, and prostate cancer. Our laboratory is also investigating a new receptor signaling pathway involving liver x receptor (LXR), its role in lipid metabolism and altered signaling in cancer. We have synthesized new potent synthetic LXR agonists that may be useful for treatment of cardiovascular and cerebrovascular diseases as well as cancer.
Molecular mechanisms of androgen actions
In 1968, studies from our laboratory showed that in certain androgen-sensitive tissues the major testicular androgen, testosterone, acts as a prohormone for the production of a more active androgen, 5alpha-dihydrotestosterone (DHT). Pharmaceutical companies have made synthetic inhibitors of 5alpha-reductase, such as Proscar (finasteride) and Avodart (dutasteride) for treatment of benign prostate hyperplasia, and Propecia for male pattern baldness. In our laboratory, we discovered androgen receptors (AR), which interact specifically with DHT and other natural and synthetic androgens to elicit a cell’s response to androgens. Antiandrogens used to treat androgen-dependent disorders were shown to inhibit this interaction. Our cloning of the cDNA for rat and human ARs made it possible to analyze the role of different AR domains in eliciting androgenic responses and to show that many androgen-insensitivity syndromes are due to AR gene mutations
Human Prostate Cancer Cell Progression and Growth Control
The growth and development of prostate cancer is initially androgen-dependent, and androgen ablation therapies pioneered by Charles Huggins have been the standard treatment for metastatic prostate cancer. Within a few years, however, progression occurs and there is no effective treatment for recurrent prostate cancer. The molecular mechanisms that drive progression of prostate cancer cells from hormone-dependence to hormone-independence are as yet incompletely understood. The main reason for this is a lack of defined experimental models that precisely mimic clinical prostate cancer progression. We have established a clonal prostate cancer cell progression system that displays at least four distinct and requisite stages of responsiveness to androgen as cells are subjected to hormone deprivation. There is mounting evidence for the existence of different intermediate androgen-dependent and androgen-repressed stage cancer cells in clinical prostate cancer. We are investigating changes in gene expression during progression in this model.
Modulation of Lipid Metabolism by Liver X Receptors
In 1993, we discovered and cloned the cDNA for a new orphan nuclear receptor that was present in many cells types and that we named Ubiquitous Receptor or UR (also now known as Liver X Receptor beta). The UR homologue LXRalpha has a more restricted distribution and is found in high levels in liver, intestine and macrophages. LXR/UR binds oxysterols and regulates genes involved in lipid metabolism, including genes for cholesterol transporters (ABAC1), fatty acid synthesis (SREBP1) and lipid transport (Apo E). We have identified both natural and synthetic UR/LXR agonists and antagonists. The LXR agonists, Hypocholamide and Hypocholaride, designed and synthesized in our laboratory, facilitate apo E-mediated cholesterol efflux from astrocytes. Apo E and cholesterol have possible roles in the development of Alzheimer’s disease and LXR agonists may be useful in the prevention and treatment of Alzheimer’s disease. In addition, we have found these LXR agonists modulate the development of atherosclerosis in murine model of atherosclerosis. The advantage of the LXR agonists identified in our lab is that they do not activate LXR in liver, which eliminates side effects like triglyceridemia prevalent in other potent LXR agonists identified previously. These projects will significantly contribute to the development of novel drugs for the treatment of cardiovascular and Alzheimer’s diseases.
Use of LXR Agonists for Control of Cancer growth and Progression
Alterations in lipid metabolism often occur during cancer development and progression. We recently showed that expression of the cholesterol transporter ABCA1, a gene regulated by LXR, plays an important role in prostate cancer progression from androgen-dependence to androgen-independence. In androgen-dependent prostate cancer, we have found that androgens can stimulate the cancer growth by inhibiting the expression of ABCA1. In line with this observation, we were able to use LXR agonists to show that these agonists can inhibit the growth of prostate and breast cancer cells and are effective in suppressing prostate tumor xenografts growing in athymic mice. Modulation of LXR receptor signaling pathway, therefore, is a potentially new target for controlling tumor growth and progression. LXR agonists are novel chemotherapeutic drugs.