Figure 2.

Schematic diagram of mechanisms of action for LHRH-R agonists, LHRH-R antagonists, CYP17 inhibitors, and androgen receptor antagonists: (1a) LHRH-R agonists bind the LHRH-R and elicit an initial gonadotropin surge. Prolonged stimulation of LHRH-R along the hypothalamic-pituitary-gonadal axis eventually suppresses LH and testosterone. (2a) LHRH-R antagonists block interaction of LHRH with LHRH-R by directly occupying the binding sites on LHRH-R. (1b and 2b) In prostate cancer cells, LHRH-R is activated not only by LHRH-R agonists but also by LHRH-R antagonists, thereby leading to Gαi/cAMP activation. The Gαi/cAMP pathway triggers inactivation of tyrosine kinase receptors (e.g., EGF-R and IGF-1R) and interferes with downstream molecular pathways (e.g., MAPK and PI3K/AKT cascades), thus resulting in antiproliferative, apoptotic, antimetastatic, and antiangiogenic effects in prostate cancer cells. (3) CYP17 inhibitors suppress the synthesis of testosterone targeting the CYP17A. (4) AR antagonists inhibit DHT binding to the androgen receptor, thereby preventing androgen receptor nuclear translocation and subsequently blocking AR-mediated transcription. AKT, protein kinase B; AR, androgen receptor; cAMP, cyclic adenosine monophosphate; DHT, dihydrotestosterone; ERK, extracellular signal-regulated kinase; FSH, follicle-stimulating hormone; LH, luteinizing hormone; EGF-R, epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor; LHRH, luteinizing hormone-releasing hormone; LHRH-R, LHRH receptor; MAPK, mitogen-activated protein kinase; p-JNK, phospho-c-Jun N-terminal kinase; PAI-1, plasminogen activator inhibitor-1; PI3K, phosphoinositide 3-kinase; uPA, urokinase plasminogen activator.