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Androgen Receptor As a Driver of Therapeutic Resistance in Advanced Prostate Cancer Barbara Kahn, Joanne Collazo, and Natasha Kyprianou 

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Androgen Receptor As a Driver of Therapeutic Resistance in Advanced Prostate Cancer Barbara Kahn, Joanne Collazo, and Natasha Kyprianou  Int. J. Biol. Sci. 2014, Vol. 10 588 Ivyspring International Publisher International Journal of Biological Sciences 2014; 10(6): 588-595. doi: 10.7150/ijbs.8671 Review Androgen Receptor as a Driver of Therapeutic Resistance in Advanced Prostate Cancer Barbara Kahn, Joanne Collazo, and Natasha Kyprianou Departments of Urology and Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, Lexington, KY 40536, USA. Corresponding author: [email protected] © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2014.01.24; Accepted: 2014.03.01; Published: 2014.06.01 Abstract The role of the androgen receptor (AR) signaling axis in the progression of prostate cancer is a cornerstone to our understanding of the molecular mechanisms causing castration-resistant prostate cancer (CRPC). Resistance of advanced prostate cancer to available treatment options makes it a clinical challenge that results in approximately 30,000 deaths of American men every year. Since the historic discovery by Dr. Huggins more than 70 years ago, androgen deprivation therapy (ADT) has been the principal treatment for advanced prostate cancer. Initially, ADT in- duces apoptosis of androgen-dependent prostate cancer epithelial cells and regression of an- drogen-dependent tumors. However, the majority of patients with advanced prostate cancer progress and become refractory to ADT due to emergence of androgen-independent prostate cancer cells driven by aberrant AR activation. Microtubule-targeting agents such as taxanes, docetaxel and paclitaxel, have enjoyed success in the treatment of metastatic prostate cancer; although new, recently designed mitosis-specific agents, such as the polo-kinase and kine- sin-inhibitors, have yielded clinically disappointing results. Docetaxel, as a first-line chemotherapy, improves prostate cancer patient survival by months, but tumor resistance to these therapeutic agents inevitably develops. On a molecular level, progression to CRPC is characterized by aberrant AR expression, de novo intraprostatic androgen production, and cross talk with other oncogenic pathways. Emerging evidence suggests that reactivation of epithelial-mesenchymal-transition (EMT) processes may facilitate the development of not only prostate cancer but also prostate cancer metastases. EMT is characterized by gain of mesenchymal characteristics and invasiveness accompanied by loss of cell polarity, with an increasing number of studies focusing on the direct involvement of androgen-AR signaling axis in EMT, tumor progression, and therapeutic resistance. In this article, we discuss the current knowledge of mechanisms via which the AR signaling drives therapeutic resistance in prostate cancer metastatic progression and the novel therapeutic in- terventions targeting AR in CRPC. Key words: Androgen receptor, taxanes, prostate cancer, therapeutic resistance, tumor progression, castration resistance, epithelial-mesenchymal transition. men and 10% of cancer deaths in men [1]. Although Prostate Cancer Progression to Metastatic local prostate cancer is curable with radical prosta- Castration-Resistant Disease tectomy or radiation therapy, advanced prostate can- Prostate cancer is the most common malignancy cer can only be palliated with chemical or surgical diagnosed in the United States, and the second most castration. Ninety percent of men with castra- common cause of cancer-related deaths. In 2013, a tion-resistant prostate cancer (CRPC) will develop total of 238,590 new cases of prostate cancer were di- bone metastases [2]. Upon progression to CRPC, me- agnosed and 29,720 died of prostate cancer. Prostate dian survival has historically been less than 2 years cancer accounts for 28% of the cancer diagnoses in [3-5]. Advanced prostate cancer is initially treated http://www.ijbs.com Int. J. Biol. Sci. 2014, Vol. 10 589 with androgen deprivation therapy (ADT)[6]. Chem- processes necessary for their growth and survival. ical or surgical castration, defined as a serum testos- ADT as the effective treatment for prostate cancer as it terone (T) <50 ng/mL, causes temporary disease re- leads to prostate tumor regression [6]. ADT can be gression by initiating apoptosis of malignant prostate achieved surgically with orchiectomy or chemically cells and indirectly impacting the tumor microenvi- with luteinizing hormone-releasing hormone (LHRH) ronment [7, 8]. Progression to CRPC is usually identi- agonists, LHRH antagonists, or anti-androgens. fied by a rising prostate specific-antigen (PSA) despite Normal expression of gonadotropin-releasing hor- castrate levels of T, indicating aberrant androgen re- mone from the hypothalamus stimulates release of ceptor (AR) reactivation [7, 9, 10] and inhibition of luteinizing hormone (LH) from the pituitary, which apoptotic pathways [11, 12]. A complex series of mo- activates synthesis of androgens from the testes, ad- lecular events such as oncogene activation, tumor renals, and peripheral tissues. ADT decreases the suppressor gene inactivation, apoptosis evasion, in- amount of circulating T present in the serum by tratumoral androgen production, and aberrant AR 90%[26, 27], which then limits AR nuclear transloca- activation lead to the development of castration re- tion and transcriptional activation. In addition to im- sistance [13]. This article will focus on the role of an- pairing AR signaling activation, ADT induces dra- drogen deprivation and AR in the emergence of matic apoptosis in normal, benign and prostate epi- therapeutic resistance. thelial cells [7, 9, 22]. LHRH agonists and antagonists inhibit the release of LH via negative feedback inhibi- The AR Axis in the Prostate Gland tion of the hypothalamus-pituitary-adrenal/gonadal The AR is a nuclear steroid receptor transcribed axis and direct inhibition respectively. When com- from the AR gene located on Xq11-12[14, 15]. Eight pared to leuprolide, an LHRH agonist, degarelix, an exons encode four functional motifs: an ami- LHRH antagonist, had a statistically significant im- no-terminal domain, a DNA-binding domain (DBD), a provement in progression free survival and overall hinge region, and a ligand-binding domain survival [28, 29]. There were no significant differences (LBD)[16-18]. The amino-terminal domain contains a in overall survival or disease-specific survival in pa- transactivation domain, AF1, which is the primary tients with metastatic prostate cancer treated with transcriptional regulatory region, and the LBD con- bilateral orchiectomy or LHRH agonists or among tains the secondary transcriptional regulatory region, different LHRH agonists [30-33]. Though LHRH ago- AF2. The DBD is composed of two zinc fingers that nists ultimately lead to inhibition of gonadal andro- are critical to DNA recognition and binding. The gen production, they initially cause a “flare,” which hinge domain contains the nuclear localization signal should be blocked with the addition of an- that regulates translocation of the AR into the nucleus, ti-androgens [34, 35]. As competitive inhibitors of AR, which indirectly effects transcriptional activity anti-androgens compete with T and DHT for the LBD [19-21]. of AR, preventing activation of the downstream Once synthesized AR settles in an inactive form pathway [33, 34]. Extragonadal sources of androgens in the cytoplasm bound to chaperone proteins, such as however may allow consistent AR signaling activa- heat shock protein 90 (hsp90). Circulating T levels, of tion [36, 37]. testicular or adrenal origin, are sequestered by sex The testes are responsible for the production of hormone binding protein (SHBP). Dissociation from 90-95% of circulating androgens, and the adrenal SHBP and diffusion across the prostatic plasma gland contributes the remainder [26]. Adrenal cortical membrane brings T into proximity of the cytochrome cells and testicular Leydig cells convert cholesterol to p450 enzyme 5α-reductase (SRD5A1, SRD5A2), pro- pregnenolone, the primary substrate in the enzymatic ducing the cognate ligand of AR, dihydrotestosterone pathway of androgen synthesis. In the zona reticularis (DHT). The presence of SRD5A1 generates a DHT rich of the adrenal cortex, pregnenolone is converted to environment in the prostate, where DHT is more po- dihydroepiandrosterone (DHEA) by CYP17A en- tent than T and is four to five times more concentrated zyme. Small amounts of DHEA are used to produce than T[22, 23]. Thus inactive AR binds DHT, causing a androstenedione and T. In the testicle, pregnenolone conformation change that frees it from its cytoplasmic is converted to T via a series of enzymatic reactions chaperone proteins. The androgen-AR complex ho- with CYP17A, HSD3B2, and HSDB vb17B. In the modimerizes, translocates to the nucleus to bind an- LNCaP xenograft model, prostate cancer cells are ca- drogen response elements, and recruits co-activators pable of de novo intratumor production of DHT de- and co-repressors, which then stimulate transcription spite castrate levels of serum T, making it a poor sur- of androgen-dependent proteins [5, 24, 25]. rogate marker of total body androgen levels [7, 38, 39]. Prostate glandular epithelial cells depend on The residual DHT in castration-resistant prostates on androgens to stimulate androgen-dependent cell ADT is lower than that
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