Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 31–36 Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer Jacqueline Moreno, Aruna V. Krishnan, David Feldman ∗ Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA Abstract Calcitriol (1,25-dihydroxyvitamin D 3 ) inhibits the growth and stimulates the differentiation of prostate cancer (PCa) cells. The effects of calcitriol are varied, appear to be cell-specific and result in growth arrest and stimulation of apoptosis. Our goal was to define the genes involved in the multiple pathways mediating the anti-proliferative effects of calcitriol in PCa. We used cDNA microarray analysis to identify calcitriol target genes involved in these pathways in both LNCaP human PCa cells and primary prostatic epithelial cells. Interestingly, two of the target genes that we identified play key roles in the metabolism of prostaglandins (PGs), which are known stimulators of PCa cell growth and progression. The expression of the PG synthesizing cyclooxygenase-2 (COX-2) gene was significantly decreased by calcitriol, while that of PG inactivating 15-prostaglandin dehydrogenase gene (15-PGDH) was increased. We postulate that this dual action of calcitriol would reduce the levels of biologically active PGs in PCa cells decreasing their proliferative stimulus and contribute to the growth inhibitory actions of calcitriol. In addition, we propose that calcitriol can be combined with non-steroidal anti-inflammatory drugs that inhibit COX activity, as a potential therapeutic strategy to improve the potency and efficacy of both drugs in the treatment of PCa. © 2005 Elsevier Ltd. All rights reserved. Keywords: CYP24; CYP27B1; VDR; cDNA arrays; Target genes; Prostaglandins; 15-PGDH; COX-2; NSAIDs 1. Introduction Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer death in North American men. Primary therapy to treat PCa involves the surgical removal of the prostate or radiation therapy. However, in many men the cancer progresses to advanced or metastatic disease. Androgens play a crucial role in the development, growth and maintenance of the prostate. Most patients with metastatic PCa who have failed the primary therapy, receive drugs that block the production of andro- gens [1]. Although most men have a good initial response to the androgen deprivation therapy, almost all of them will eventually relapse after an average of 2–3 years. This progression develops when the cancer has evolved from androgen-dependent to androgen-independent PCa (AIPC) with limited treatment options and becomes ultimately lethal. 1,25-Dihydroxyvitamin D 3 (calcitriol), the active metabolite ∗ Corresponding author. Tel.: +1 650 725 2910; fax: +1 650 725 7085. E-mail address: feldman@cmgm.stanford.edu (D. Feldman). of Vitamin D, has emerged in recent years as a promising therapeutic agent in the treatment of PCa [2–11]. Calcitriol is an important regulator of calcium homeostasis and bone metabolism through its actions in intestine, bone, kidney and the parathyroid glands [12]. In addition to these clas- sical actions, calcitriol also exerts anti-proliferative and pro- differentiating effects in a number of tumors and malignant cells including PCa raising the possibility of its use as an anti-cancer agent. 2. Calcitriol and prostate cancer 2.1. Epidemiological and genetic studies PCa development has been shown to be associated with age, genetic factors and race [1]. Various studies indicate that dietary [13] and environmental factors also play a role in PCa genesis. Epidemiological data provide a strong correlation between the exposure to sunlight and the prevalence of cer- tain cancers, particularly prostate cancer [14]. Since UV light 0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.06.012