European Urology European Urology 43 (2003) 301±308 TheSurvivalEffectofProlactinonPC3ProstateCancerCells Alain Ruf®on a,* , Kaltoom A. Al-Sakkaf b , Barry L. Brown b , Colby L. Eaton c , Freddie C. Hamdy c , Pauline R.M. Dobson b a Department of Urology, Hopital Jules Courmont, Chemin du Grand Revoyet, 69495 Pierre Be Ânite Cedex, France b Academic Unit of Endocrinology, Division of Genomic Medicine, Institute for Cancer Studies, Shef®eld University Medical School, Shef®eld, UK c Section of Urology, Division of Surgical Sciences and Anaesthesia, Institute for Cancer Studies, Shef®eld University Medical School, Shef®eld, UK Accepted 8 January 2003 Abstract Objectives: Recent studies suggest a paracrine/autocrine loop involving prolactin (PRL) within the human prostate. The aims of this study were to determine the effects of PRL on the growth and survival of prostate cancer cells and the intracellular signalling mechanisms underlying such effects. Methods: The effect of PRL on proliferation of LNCaP, PC3 and DU145 was assessed by Coulter counting. The effect of PRL on TRAIL-, staurosporine- and ¯avopiridol-induced apoptosis was assessed by Timelapse microscopy and Annexin V binding. The status of the PRL receptor (PRL-R) and Akt/PKB (protein kinase B) activity were assessed by Western blotting. Results: All three cell lines expressed both the short and long forms of the PRL receptor. Although, no signi®cant effect of PRL on the proliferation of these cells was found, PRL partially inhibited TRAIL-induced apoptosis in PC3 cells. PRL also enhanced the phosphorylation of Akt/PKB in these cells. Conclusions: PRL had no signi®cant effect on the proliferation of PC3, DU145 and LNCaP, but inhibited TRAIL- induced apoptosis in PC3 cells, possibly via enhanced Akt/PKB phosphorylation in PC3 cells. Further investigations are underway to determine the survival effect of PRL on the other two prostate cancer cell line. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Prostate cancer; Apoptosis; Akt; Prolactin; TRAIL 1. Introduction The fact that prolactin (PRL) in¯uences the devel- opment of the prostate gland has been known for a long time [1±3]. It is now clear that PRL stimulates the proliferation and differentiation of prostate cells [4]. In transgenic mice overexpressing the prolactin gene, the dorso-lateral and ventral lobes were 9±20 times larger than in controls, due both to an increased secretion from the prostate [5] and to an increase in the number of cells. It has been proposed that PRL may promote prostate growth in synergy with androgens, perhaps by increas- ing the uptake of testosterone into prostate cells [6±8]. However, the possible involvement of PRL in pros- tate cancer is less clear. It is now well established that non-androgenic factors, such as peptide hormones and growth factors are involved in prostate cell growth regulation [9]. Therefore, the fact that PRL levels rise (or at least are stable) in elderly people, whereas other hormones or growth factors (like androgens and growth hormone) decrease, is an argument for a possible role of PRL in both Benign Prostatic Hyperplasia and prostate cancer. The results of several studies tempered this enthusiasm. Firstly, clinical studies using bromocriptine in metastatic prostate carcinoma were discontinued because of the lack of response [10,11]. Secondly, recent studies found no correlation between prostate cancer and a high systemic level of PRL [12±15]. However, these ®ndings can be argued in the light of other important observations. It has been shown that PRL can be synthesised in a large number of tissues [16], including the prostate. Moreover, the existence of functional PRL receptors (PRL-R) in the prostate has been demonstrated in humans and in animal models * Corresponding author. Tel. 33-4-7886-13-17; Fax: 33-4-7886-33-34. E-mail address: alain.ruf®on@wanadoo.fr (A. Ruf®on). 0302-2838/03/$ ± see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0302-2838(03)00038-1