U J All Final for WEB.pdf 747Vol. 10 | No. 1 | Winter 2013 |U R O LO G Y J O U R N A L Purpose: To discuss the role of membrane androgen receptors and to investigate the potential role of testosterone-albumin conjugate in the prostate cancer (PCa) treatment. Materials and Methods: Results: The androgen receptor plays a critical role in both development and progression of - vival of prostatic cells to an independent autocrine process. This malignant conversion is due - lial cells. Thus, treatments for neoadjuvant, adjuvant, and recurrent disease, all center on the evidence of a direct apoptotic action induced by activation of the membrane androgen receptor by testosterone-albumin conjugates. Conclusion: membrane androgen receptors in the androgen-independent PCa cell is important on the one - - lishment of activators of membrane androgen receptors. In addition, study of the testosterone- Keywords: androgen receptors, testosterone, prostatic neoplasms, therapeutics Department of Urology, “Tzaneio” General Hospital of Piraeus, Piraeus, Greece Konstantinos Stamatiou, Nikolaos Pierris REVIEW Could Testosterone Have a Therapeutic Role in Prostate Cancer? Corresponding Author: Konstantinos Stamatiou, MD 2 Salepoula St., 18536 Piraeus, Greece Tel: +30 210 459 2387 E-mail: stamatiouk@gmail.com Received April 2012 Accepted September 2012 748 | Review INTRODUCTION Steroid Hormone Receptors T -cer (PCa) development, and its progression is con- duration of ADT, ADT formulation, or disease status. Fur- thermore, there is evidence that even hormone-refractory PCa cells continue to be affected by androgen signaling de- spite ADT. This fact indicates that androgen receptors are the key element in PCa development rather than androgens themselves. According to current literature, steroid molecules, such as testosterone, enter the target cell, eg, of the prostate gland, by passive transport through the cell membrane by diffusion. - sulting in the formation of a DNA binding area. This phe- nomenon results from the conversion of testosterone into its - hydrotestosterone and receptor) migrates to the nucleus and triggers off the transcription of genes into mRNA to produce functions.(2) The time from initiation until the completion of - - - transporting proteins, it acts on local cytoplasmic channels leading to the activation of cyclic AMP. This activity takes - it represents an additional function of the classic cytoplasmic receptors. Indeed, the manifestation of rapid non-genomic phenomena resulting from steroid hormone signaling may be for steroid hormones possibly located in the cell membrane, - (6) Such steroid hormone re- rapid non-genomic phenomena, have already been described - sic receptors (monocytes, T-lymphocytes). Merely as of a the cell membrane of cells carrying classic androgen recep- tors, such as osteoblasts and cells of the prostatic glandular epithelium. have through these receptors has not been fully elucidated. The established mechanisms up to date are kinase regula- tion, cyclic nucleotide modulation, and intracellular calcium changes. The aforementioned activities are very rapid: progesterone minute. Testosterone increases intracellular calcium in and leads to the synthesis of the molecular messengers, such as - 749Vol. 10 | No. 1 | Winter 2013 |U R O LO G Y J O U R N A L in only ten seconds.(22) This activity is dose-related, it is not - span of time. - terone on muscle cells of male rats and of androstenedione on human porcine ovarian cells resulted in a similar rise in intracellular calcium and trebling of the levels of IP3. The rise in intracellular calcium seen in the above-mentioned - man cells. Rapid androgen action has also been described in (26,27) as in the neuronal cells(7) and hepatocytes. The fact that the above-mentioned functions have been dem- onstrated in cells lacking a functional nucleus, such as eryth- are not inhibited by nuclear androgen receptor inhibitors (hy- functions are affected by non-classic steroid receptors. - androgen stimulation despite their lack of classic androgen MATERIALS AND METHODS searching the MEDLINE database of the National Library cytoplasmic androgen receptor, and membrane androgen re- conjugate, and prostate cancer treatment”. References in the not included in the MEDLINE or PubMed search. RESULTS Androgen Receptors and Prostate Cancer - portant factor affecting the proliferation and function of the normal prostate gland. Prostatic glandules and prostatic pores cells do not carry classic androgen receptors, but are differen- classic androgen receptors, into secreting and neuroendocrine - Androgens play an important role in the development and maintenance of both normal and neoplastic prostate tissue. - dle of the previous century since the discovery of androgen deprivation therapy for PCa by Huggins and Hodges. Andro- gen blockade in its complete form (elimination of testicular testosterone and inhibition of the classic androgen receptor) remains the golden standard management of metastatic PCa and is also used as adjuvant and neo-adjuvant therapy in ad- vanced cancer. Unfortunately, despite an initial positive response to androgen deprivation therapy, many cancers pro- gress to androgen-independent or androgen-resistant forms and relapse ultimately. Because of this, androgen deprivation The androgen receptors themselves are responsible for the androgens, it is today believed that androgen receptors un- androgen-resistant state the levels of detectable prostate an- drogen receptors are reduced, there are strong evidences for the presence of androgen receptors in androgen-independent cancers, those under androgen deprivation, and cancers re- lapsing during androgen deprivation therapy. - - tion or re-emergence of the androgen receptor. Further- more, the observation of an intermediate state of hormone - sistance (androgen deprivation syndrome) lends merit to the - festation of a mutation phase of the androgen receptor. Testosterone and Prostate Cancer | Stamatiou and Pierris 750 | Review - (36) Although, as already mentioned, in the hormone-resistant state the levels of detectable prostate androgen receptors are reduced and the androgen-resistant cells multiply irrespec- - gen receptors for their survival.(37) Indeed, if by intracellular - duced beyond a certain point, these cells stop multiplying and die. This property characterizes the non-classical cells. The Role of Androgens and Non-Classic Androgen Re- ceptors As opposed to the classic cytoplasmic androgen recep- tor, membrane androgen receptors have not been studied non-genomic functions, including kinase regulation, cyclic nucleotide modulation, and intracellular calcium changes. The latter seems to be related to the apoptotic process and programmed cell death. Studies on both cultured human PCa human PCa provided strong evidence of an immediate anti- neoplasmic activity after the activation of membrane andro- - of LNCaP cancer cells, induction of apoptosis, release of the reduction in migration, adhesion, and development of the The fact that the above-mentioned antineoplastic functions administration both in iAR-negative human cancer cells - nucleotide) positive for cytoplasmic androgen receptors cul- - tors possibly at the level of membrane androgen receptors. - ready mentioned. - anticancer activity. In fact, albumin inhibits the production of actin and therefore affects the formation of the cytoskel- eton contributing thus to the apoptotic remission of human PCa cells. On the other hand, testosterone and other - the migration of PCa cells by activation of estrogen receptor B (ERB) and the resultant signaling. Another biochemi- - tivation of the receptor of tumor necrosis factor (TNF) RSF6 and produce its end product. - ert anticancer properties in organs other than the prostate. Activation of membrane androgen receptors by the testoster- of cancer cells. Apoptotic Regression of Prostate Cancer Through Acti- vation of Membrane Androgen Receptors of membrane androgen receptors by the testosterone-albu- through mobilization of intracellular calcium, on cytoskel- etal actin. The latter is of vital importance for cell survival as it is a structural element of the cellular substrate and thus cytoskeleton through membrane androgen receptors has not 751Vol. 10 | No. 1 | Winter 2013 |U R O LO G Y J O U R N A L been fully elucidated. - ing PCa cells (LNCaP) to the testosterone-bovine albumin - - changes in its assembly. - - oid hormones, such as the androgens, modify the action of cytoskeletal reassembly. control of cellular development, cell survival, malignant transformation, and invasiveness appears to be PI-3 kinase, outcomes depending on the direction. Activation of PI-3 membrane androgen receptors of human cancer LNCaP cells - cytoskeletal actin and the formation of cell membrane evagi- Such cytoskeletal reas- sembly has been linked to malignant transformation, cellular migration, and cancer invasiveness. - PCa. - - - PI-3 kinase. - cantly affect the invasive potential of cancer cells (on the one - - lipodia), in fact their role in cellular response differs depend- ing on cell type. In epithelial cells, such as in the prostate, cells and inhibits migration and invasion. It is therefore possible that the development or inhibition of development of the cancer cell depends on the direction of activation of PI- - man cancer LNCaP cells) and the different outcome depend- ing on the case seem to support the above hypothesis. The phenomenon is dose-dependent and time-dependent. - culture medium. According to recent observations, chron- ic stimulation of membrane androgen receptors indeed leads to inhibition of cell development and to apoptosis through chronic androgen deprivation seems to increase the resist- ance of cancer cells to the induction of apoptosis through the same mechanism. Despite the undoubtable observation that membrane receptors are the mediators of the above ac- membrane androgen receptors remain unclear. CONCLUSION - optosis through activation of the membrane androgen recep- tors in the androgen-independent PCa cell is important on the one hand because future manipulation of this mechanism can characteristics of PCa, and on the other hand, can contrib- ute to the establishment of activators of membrane androgen receptors. 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