Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

Departments of Pathology, Urology, Radiation Oncology and Wilmot Cancer Center, George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, NY, USA.
Oncogene (Impact Factor: 8.46). 06/2010; 29(25):3593-604. DOI: 10.1038/onc.2010.121
Source: PubMed


Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormone-refractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR over-expression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells.

Download full-text


Available from: Yuzhuo Wang
  • Source
    • "These results substantiate in vitro studies showing that enforced expression of AR in AR-negative PCa cells decreases the metastatic/invasive potential of the cells [26, 29–35]. In a recent paper evaluating the role of androgen signalling in epithelial-mesenchimal transition, Zhu and Kyprianou [36] demonstrated that overexpression of AR in PCa cell lines suppresses androgen-induced epithelial-mesenchimal transition, suggesting that downregulation of AR occurring in androgen-deprived condition [37] may facilitate mesenchimal transition and promote metastasis [36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PCa) is the most common malignancy in elderly men. The progressive ageing of the world male population will further increase the need for tailored assessment and treatment of PCa patients. The determinant role of androgens and sexual hormones for PCa growth and progression has been established. However, several trials on androgens and PCa are recently focused on urinary continence, quality of life, and sexual function, suggesting a new point of view on the whole endocrinological aspect of PCa. During aging, metabolic syndrome, including diabetes, hypertension, dyslipidemia, and central obesity, can be associated with a chronic, low-grade inflammation of the prostate and with changes in the sex steroid pathways. These factors may affect both the carcinogenesis processes and treatment outcomes of PCa. Any treatment for PCa can have a long-lasting negative impact on quality of life and sexual health, which should be assessed by validated self-reported questionnaires. In particular, sexual health, urinary continence, and bowel function can be worsened after prostatectomy, radiotherapy, or hormone treatment, mostly in the elderly population. In the present review we summarized the current knowledge on the role of hormones, metabolic features, and primary treatments for PCa on the quality of life and sexual health of elderly Pca survivors.
    Full-text · Article · Mar 2014 · International Journal of Endocrinology
  • Source
    • "In addition, AR was identified as a novel therapeutic target in UUTUCs to increase the efficacy of chemotherapeutic agents. Therapies targeting the androgen-receptor signaling axis have been used for the treatment of prostate cancer with various strategies (42,43) and may be suitable for application in the treatment of UUTUCs. Thus, the combination of AR targeted therapy with chemotherapy may increase the efficacy of therapy to cure invasive and metastatic forms of cancer previously considered to be difficult to treat. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Upper urinary tract urothelial carcinomas (UUTUCs) represent relatively uncommon yet devastating tumors that affect more males than females. However, the correlation between gender difference and disease progression remains unclear. Androgen and the androgen receptor (AR) were previously hypothesized to account for the gender difference in the incidence of urothelial carcinomas; however, the role of AR in the development and progression of UUTUCs is not well understood. In addition, although UUTUCs are responsive to chemotherapy, various responses are presented among patients. Therefore, the aim of the present study was to determine the role of AR in the response of UUTUC cells to chemotherapeutic drugs. In this study, AR overexpression in UUTUC cells (BFTC 909) was identified to reduce the cytotoxic effect of chemotherapeutic drugs, including doxorubicin, cisplatin and mitomycin C and protected cells from drug-induced death. The expression of ABCG2, an ATP-binding cassette half-transporter associated with multidrug resistance, was increased in AR-overexpressing BFTC cells. In addition, use of the AR degradation enhancer, ASC-J9(®), repressed the AR effect on increasing cell viability under drug treatment. In summary, results of the present study indicate that the status of AR expression levels in UUTUCs may be a significant factor in affecting the efficacy of chemotherapy and classic chemotherapeutic drugs and AR targeted therapy may provide a novel potential therapeutic approach to improve treatment of UUTUCs.
    Full-text · Article · Apr 2013 · Oncology letters
  • Source
    • "Our data suggest that long-term androgen-depletion may induce downregulation of AR and PSMA which may lead to a diagnostically and therapeutically elusive androgen-independent disease-state. These new data provide additional knowledge of androgen-independent prostate cancer progression compared to previous studies, which primarily focused on changes in AR ligand binding specificity that may result from gene structure changes (e.g., mutation, amplification, or spliced variant expression) or AR ligand-independent activation arising from alternative signal pathways that activate AR activity at the castration level of androgen (2,24). With respect to PSMA, it is thought that increased expression is correlated with prostate cancer progression, especially in recurrent, metastatic cancers after androgen deprivation therapy (25,26). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Emergence of androgen-independent cancer cells during androgen deprivation therapy presents a significant challenge to successful treatment outcomes in prostate cancer. Elucidating the role of androgen deprivation in the transition from an androgen-dependent to an androgen-independent state may enable the development of more effective therapeutic strategies against prostate cancer. Herein, we describe an in vitro model for assessing the effects of continuous androgen-deprivation on prostate cancer cells (LNCaP) with respect to the expression of two prostate-specific markers: the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Compared with androgen-containing normal growth medium, androgen-deprived medium apparently induced the concomitant downregulation of AR and PSMA over time. Decreased protein levels were confirmed by fluorescence imaging, western blotting and enzymatic activity studies. In contrast to the current understanding of AR and PSMA in prostate cancer progression, our data demonstrated that androgen-deprivation induced a decrease in AR and PSMA levels in androgen-sensitive LNCaP cells, which may be associated with the development of more aggressive disease-state following androgen deprivation therapy.
    Full-text · Article · Oct 2012 · International Journal of Oncology
Show more