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J M Bentel and W D Tilley

Introduction

Prostate cancer constitutes a major health issue in Western countries where it is now the most frequently diagnosed invasive tumour and second leading cause of cancer deaths (Wingo et al. 1995). Androgen action in prostate cancers, as in the normal prostate gland and other target organs, is mediated by the androgen receptor (AR), a ligand-activated nuclear transcription factor that is a member of the steroid/thyroid hormone receptor gene superfamily (O'Malley 1990, Truss & Beato 1993). Although the human AR has only recently been cloned (Chang et al. 1988, Lubahn et al. 1988, Trapman et al. 1988, Tilley et al. 1989), specific actions of androgens on the growth, differentiation and function of the prostate gland were elucidated early this century. In 1941, Huggins and Hodges demonstrated that, similar to non-malignant prostate, prostate cancers were androgen-responsive and that tumour regression was evident following removal of testicular androgens by castration. More than

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A Stigliano, O Gandini, L Cerquetti, P Gazzaniga, S Misiti, S Monti, A Gradilone, P Falasca, M Poggi, E Brunetti, A M Aglianò and V Toscano

Introduction The prostate is an androgen-regulated organ, which has led to longstanding interest in the role of androgens in prostate carcinogenesis ( Sandberg 1980 ). Prostate cancer is one of the most common malignancies among men

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Ashley Gray, William J Aronson, R James Barnard, Hemal Mehta, Junxiang Wan, Jonathan Said, Pinchas Cohen and Colette Galet

Introduction Prostate cancer is one of the leading causes of cancer death among men in the United States ( Kohler et al . 2011 ). Insulin-like growth factor 1 (IGF1) has been implicated as a possible factor contributing to prostate cancer risk. The

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M Arvigo, F Gatto, M Ruscica, P Ameri, E Dozio, M Albertelli, M D Culler, M Motta, F Minuto, P Magni and D Ferone

interaction on cell membrane and cell proliferation in a cell line constitutively expressing four out of five SSTRs, the androgen-dependent prostate cancer cell line LNCaP ( Ruscica et al . 2010 ), and in a cell line constitutively expressing three out of

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PN Span, CM Thomas, JJ Heuvel, RR Bosch, JA Schalken, L vd Locht, EJ Mensink and CG Sweep

Expression of human chorionic gonadotrophin (hCG) is associated with trophoblastic, testicular and other malignancies such as bladder, pancreatic, cervical, breast and prostate cancer. In the prostate, however, hCG expression, associated with neuroendocrine cells, is also found in normal tissue. Of the six highly homologous genes that all encode the beta-subunit of hCG, the beta 7 gene is reportedly the only gene expressed in several non-transformed tissues. The beta 3, 5 and 8 genes would be variably expressed in malignant tissue and placenta, but not in normal tissue. To assess to what extent this expression difference can also be found in the prostate, we compared the levels of the different hCG beta transcripts in concurrent normal and cancerous prostate tissues obtained from 17 patients. To this end, we developed a Taqman real-time fluorescent RT-PCR assay for hCG beta, and a quantitative assay specific for the beta 3, 5 and 8 genes, modified from the molecular beacon principle. This latter assay proved highly specific and capable of reliably distinguishing between these hCG beta transcripts that differ in only one nucleotide. Surprisingly, median expression levels of hCG beta were lower in prostate cancer when compared with normal tissue from the same patient. In contrast, hCG beta 3, 5 and 8 transcripts were found in normal tissue and did not differ in prostate cancer, arguing against a specific role of these transcripts in the development of prostate cancer.

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PL Jeffery, AC Herington and LK Chopin

This study has examined the expression of two new facets of the growth hormone axis, the growth hormone secretagogue receptor (GHS-R) and its recently identified putative natural ligand ghrelin, in prostate cancer cells. GHS-R 1a and 1b isoforms and ghrelin mRNA expression were detected by RT-PCR in the ALVA-41, LNCaP, DU145 and PC3 prostate cancer cell lines. A normal prostate cDNA library expressed GHS-R1a, but not the 1b isoform or ghrelin. Immunohistochemical staining for the GHS-R 1a isoform and ghrelin was positive in the four cell lines studied. PC3 cells showed increased cell proliferation in vitro in response to ghrelin to levels 33% above untreated controls, implying a potential tumour-promoting role for ghrelin in this tissue. This study is the first to demonstrate the co-expression of the GHS-R and ghrelin in prostate cancer cells. It is also the first study to provide evidence that a previously unrecognised autocrine/paracrine pathway involving ghrelin, that is capable of stimulating growth, exists in prostate cancer.

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M Baijal-Gupta, MW Clarke, MA Finkelman, CM McLachlin and VK Han

PSP94 (beta microseminoprotein, beta MSP) is one of the three major proteins secreted by the normal human prostate gland. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blotting, PSP94 transcripts were shown in human endometrium, myometrium, ovary, breast, placenta and in the human endometrial cancer cell lines KLE and AN3 CA. Primers used in these studies were specific for human prostate PSP94, and were derived from its flanking non-coding regions. The results were confirmed by sequence analysis of two independently derived clones from normal human breast tissues and the other two from KLE cells respectively. The sequences were identical with the coding sequence of human prostate PSP94 cDNA. Using RNA from the endometrial tissues, two different transcripts of approximately 487 bp, equivalent to prostate PSP94 and approximately 381 bp, corresponding to prostate PSP57, its alternately spliced form, were amplified by RT-PCR. Human ovary, breast, placenta and endometrial cancer cell lines (KLE, AN3 CA), however, showed only the full length, approximately 487 bp, PSP94 transcript. We further demonstrated by in situ hybridization that PSP94 mRNA is expressed specifically in the glandular epithelial cells, and not in the stroma of both the human endometrial and breast tissues. Further, using image analysis of in situ hybridization data, the levels of PSP94 mRNA in the cycling endometrial tissues and in breast confirmed the differential levels of expression in the cycling endometrium (P<0.005). This study distinctly demonstrated significant expression of PSP94 mRNA in human uterine, breast and other female reproductive tissues as well in the endometrial cancer cell lines, suggesting that it may have a role in these tissues as a local autocrine paracrine factor.

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J Franklin, J Hislop, A Flynn and CA McArdle

Gonadotrophin-releasing hormone receptors (GnRH-Rs) are found in cancers of reproductive tissues, including those of the prostate, and gonadotrophin-releasing hormone (GnRH) can inhibit growth of cell lines derived from such cancers. Although pituitary and extra-pituitary GnRH-R transcripts appear identical, their functional characteristics may differ. Most extra-pituitary GnRH-Rs have low affinity for GnRH analogues and may not activate phospholipase C or discriminate between agonists and antagonists in the same way as do pituitary GnRH-Rs. Here we have assessed whether GnRH-Rs expressed exogenously in prostate cancer cells differ functionally from those of gonadotrophs. We found no evidence for endogenous GnRH-Rs in PC3 cells, but after infection with adenovirus expressing the GnRH-R (Ad GnRH-R) at 10 plaque forming units (p.f.u.)/cell or greater, at least 80% of the cells expressed GnRH-Rs. These sites had high affinity (K(d )for [(125)I]Buserelin 1.1+/-0.4 nM) and specificity (rank order of potency: Buserelin> GnRH>>chicken (c) GnRH-II), and mediated stimulation of [(3)H]inositol phosphate (IP) accumulation. Increasing viral titre from 3 to 300 p.f.u./cell increased receptor number (2000 to 275 000 sites/cell respectively) and [(3)H]IP responses. GnRH also caused a biphasic increase in the cytoplasmic Ca(2+) concentration in Ad GnRH-R-infected cells but not in control cells. Mobilization of Ca(2+) from intracellular stores contributed to the spike phase of this response whereas the plateau phase was dependent upon Ca(2+) entry across the plasma membrane. This effect on Ca(2+) and stimulation of [(3)H]IP accumulation were both blocked by the GnRH-R antagonist, Cetrorelix. In addition, GnRH reduced cell number (as measured in MTT activity assays) and DNA synthesis (as measured by [(3)H]thymidine incorporation) in Ad GnRH-R-infected cells (but not in control cells). This effect was mimicked by agonist analogues and inhibited by two antagonists. Thus, when exogenous GnRH-Rs are expressed at a density comparable to that in gonadotrophs, they are functionally indistinguishable from the endogenous GnRH-Rs in gonadotrophs. Moreover, expression of high affinity GnRH-Rs can facilitate a direct anti-proliferative effect of GnRH agonists on prostate cancer cells.

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R Rajah, A Khare, PD Lee and P Cohen

Cells are known to undergo apoptosis when cultured in high serum concentrations. However, the serum factors responsible for this induction of apoptosis have not been identified. The IGF-binding protein-3 (IGFBP-3), a negative growth regulator, is found at concentrations of 5 microgram/ml in serum. We have recently demonstrated that IGFBP-3 induces apoptosis in PC-3 cells, a prostate cancer cell line, at a concentration of 500 ng/ml. In this communication, we demonstrate the role of IGFBP-3 as one of the apoptosis-inducing agents in high serum concentrations. Treatment of PC-3 cells with increasing concentrations (40% to 90%) of intact human serum (HS) resulted in a dose-dependent decrease in cell growth. Valinomycin, an ionophore, was used as a positive control to measure the induction of apoptosis by serum treatment in PC-3 cells. Treatment with 90% serum showed significant suppression of growth (P<0.001) compared with the effect of 10% serum. Treatment with increasing concentrations of HS (40% to 90%) resulted in a dose-dependent increase in apoptosis. Treatment with 90% HS showed a 10-fold increase in apoptotic index compared with cells treated with 10% HS. Treatment of PC-3 cells with IGFs and IGFBP-3-depleted 90% human sera (depleted serum=DS) demonstrated significantly lower levels of apoptosis (50% reduction in the effect of 90% HS) suggesting a role of IGFBP-3 in inducing apoptosis in high serum concentration. Furthermore, treatment with DS supplemented with recombinant IGFBP-3 (500 ng/ml) brought the apoptotic index down close to the level of apoptosis induced by 90% intact serum treatment (P<0.001). However, DS supplemented with physiological concentrations of IGFs (500 ng/ml) showed only partial recovery of cell survival demonstrated by 90% DS. This data indicates that IGFBP-3 is one of the factors in serum that is responsible for high-serum-induced apoptosis.

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Laura E Pascal, Khalid Z Masoodi, June Liu, Xiaonan Qiu, Qiong Song, Yujuan Wang, Yachen Zang, Tiejun Yang, Yao Wang, Lora H Rigatti, Uma Chandran, Leandro M Colli, Ricardo Z N Vencio, Yi Lu, Jian Zhang and Zhou Wang

formation in C. elegans ( Cai et al. 2011 ). In advanced prostate cancer, EAF2 protein was downregulated ( Xiao et al. 2003 , Ai et al. 2013 , Pascal et al. 2013 ); and, overexpression of EAF2 in prostate cancer cell lines induced apoptosis and