928P - Lhrh Agonist-Induced Suppression of the Androgen Synthesis Pathway in Prostate Cancer

Abstract

Background: Standard first-line therapy for advanced prostate cancer (PC) includes the use of a luteinizing hormone releasing hormone (LHRH) agonist. While the primary site of action for these agents is the pituitary-hypothalamic-gonadal axis, receptors for LHRH are also present in the membrane of PC cells and mediate a direct anti-tumor effect. The mechanism of this effect has been largely unexplored and may harbor a context of vulnerability. Previously, we have demonstrated that luteinizing hormone (LH) increases de novo steroidogenesis in PC cells and silencing of the LH receptor leads to downregulation of steroidogenesis. Here, we examined the impact of LHRH agonists on this process at the cellular level. Methods: LNCaP PC cells were treated with the LHRH agonist buserelin for 8 hours in the presence or absence of the LHRH antagonist antide. Gene expression of LH and androgen synthesis enzymes was quantified by real-time polymerase chain reaction and protein expression was measured with Western blot. Cell proliferation was assessed in these cells using MTS assays. Results: The LHRH agonist buserelin significantly suppressed the gene expression of LH and the androgen synthesis enzymes AKR1C1, AKR1C2, AKR1C3, CYP11A1 and RDH5 (p<0.05). Protein expression of LH, AKR1C1, AKR1C3 and CYP17A1 was also inhibited by buserelin treatment (p<0.05). Buserelin also suppressed LNCaP cell proliferation in a dose-dependent manner (p<0.05). The suppressive effects of buserelin on gene expression, protein expression and cell proliferation were mitigated by the LHRH antagonist antide. Conclusion: These data implicate the LHRH agonist buserelin in the direct inhibition of de novo tumoral steroidogenesis, which may be mediated by suppression of LH. The LH pathway warrants further investigation as a therapeutic target. The treatment of advanced prostate cancer relies on androgen deprivation, often with an LHRH agonist. These agents induce the downregulation of LHRH receptors in pituitary gonadotrophs that ultimately leads to a decrease in gonadal testosterone synthesis. LHRH receptors are also highly expressed on prostate cancer cells. Unlike their pituitary counterparts, prolonged exposure to LHRH agonists does not lead to their downregulation. The role of these tumoral LHRH receptors remains unclear. Our data suggest that the LH pathway may play a role in tumoral steroidogenesis. Here, we explore the impact of LHRH agonist therapy on LH expression and tumoral steroidogenesis.