Molecular mechanisms involved in the transition of prostate cancer cells from androgen dependent to castration resistant state

Prostate cancer is an internationally important health problem of the man, particularly in developed countries. Currently the main line of treatment for prostatic cancer is based on androgen deprivation. The androgen blockade treatment is initially effective on androgen dependent cancer, but the disease relapses within a period of around two years with a more aggressive form named castration resistant cancer. The growth and expansion of castration resistant cancer are not dependent on androgen supply anymore and thus is more difficult to treat. Understanding the molecular mechanism involved in the transition of prostate cancer cells from androgen dependent to androgen independent state is the key for designing a biologically appropriate strategy for a more effective treatment. Currently, several different theories have been brought about to address this transition process and based on these theories, several lines of treatments were introduced for the castration resistant disease. Despite the advances in our knowledge of prostate cancer cell transition, no current theoretical explanation can satisfactorily cover all aspects of this transition process and no curative treatment of the castration resistant disease is available. In this review, we summarized and commented several major current theories to explain the molecular pathology on the transition of prostate cancer cells from androgen dependent to androgen independent state. In addition, we have also briefly introduced an alternative mechanism to explain this complicated transition process. an important factor in the development and function of the prostate gland. Androgen receptor (AR) is a steroid receptor and a member of the larger nuclear receptor family which act as a transcription factor after binding to various binding sites. It is located on Chr Xq12 and made of 8 exons and has 8 splice variants (Figure 1) and it consists of a DNA binding domain (DBD), a ligand-binding domain (LBD), two transcriptional activation domains and a hinge region which introduce nuclear localization [2-4]. In the absence of androgen, AR is located in the cytoplasm with chaperone proteins such as HSP90, HSP40 and HSP23 [5]. When androgen binds to the ligand binding site, a conformational change will happen in the structure of the gene. The AR then transfer to the nucleus and forms a homodimer which then bind to the regulatory regions of other genes that are critical for the normal function and differentiation of prostate [5]. The genes regulating AR may be critical in the development of PCa but their role is not completely clear. Androgendeprivation therapy (ADT) is the main treatment for localized PCa. Although the initial response to treatment is very good but the relapse of a more resistance and aggressive type of cancer is inevitable and invariable. Although the castration resistance cells are androgen independent, it is clear that signalling through AR continues to be effective for tumour growth under castrations condition. This is called castration-resistant prostate cancer (CRPC) which is still signalling through AR but with different mechanisms. CRPC is the second most common cause of death in American men and currently is irredeemable [6]. As the CRPC is still depending on AR signalling, the current treatments are not targeting the receptors directly, but work indirectly to either reduce androgen or block the ligand binding site in the AR gene. One group of these drugs is CYP17 inhibitors (abiraterone, ketoconazole, orteronel, VN/124-1) which inhibit the enzyme that bio-synthesis androgen from its precursor [7]. MDV3100 (enzalutamide) is another group of these drugs and is a Shiva Seyed Forootan*, Syed Hussain, Vijay Aachi, Christopher S. Foster and Youqiang Ke* Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, the University of Liverpool; 5/6th Floor, Duncan Building, Daulby Street, Liverpool, L69 3GA,UK *Address for Correspondence Dr. Shiva Seyed Forootan or Professor Youqiang Ke, Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, the University of Liverpool; 5/6th Floor, Duncan Building, Daulby Street, Liverpool, L69 3GA, Uk, Tel: 0044-151-706 4152; Fax: 0044-151-706 5883; E-mail: shifor@liverpool.ac. uk or yqk@liverpool.ac. uk Submission: 08 August 2014 Accepted: 11 September 2014 Published: 15 September 2014 Reviewed & Approved by: Dr. Wen-Chin Huang, Assistant Professor of Uro-Oncology Research Program at the Department of Medicine at Cedars-Sinai Medical Center and Samuel Oschin Comprehensive Cancer Institute, USA Review Article Open Access