A novel androgen signalling pathway uses dihydrotestosterone, but not testosterone, to activate the EGF receptor signalling cascade in prostate stromal cells

作者：Oliver V L^*; Poulios K; Ventura S; Haynes J M

来源：British Journal of Pharmacology, 2013, 170(3): 592-601.

DOI：10.1111/bph.12307

• human-cultured prostatic stromal cells
• intracellular calcium
• dihydrotestosterone
• EGF
• non-genomic androgen signalling

Background and PurposeHuman prostate growth and function are tightly controlled by androgens that are generally thought to exert their effects by regulating gene transcription. However, a rapid, non-genomic steroid action, often involving an elevation of intracellular calcium ([Ca2+](i)), has also been described in a number of cell types. In this study we investigate whether androgens acutely regulate [Ca2+](i) in stromal cells derived from the human prostate. %26lt;br%26gt;Experimental ApproachHuman-cultured prostatic stromal cells (HCPSCs) were loaded with the calcium-sensitive fluorophore, fura-2-acetoxymethyl ester (FURA-2AM) (10M). Changes in [Ca2+](i) in response to the androgens, dihydrotestosterone (DHT) and testosterone, as well as EGF were measured by fluorescence microscopy. %26lt;br%26gt;Key ResultsDHT, but not testosterone (0.03-300nM), elicited concentration-dependent elevations of [Ca2+](i) within 1min of addition. These responses were blocked by the androgen receptor antagonist, flutamide (10M); the sarcoplasmic reticulum ATPase pump inhibitor, thapsigargin (1M); the inositol trisphosphate receptor inhibitor, 2-aminoethyldiphenyl borate (50M) and the PLC inhibitor, U-73122 (1M). Responses were also blocked by the L-type calcium channel blocker, nifedipine (1M), and by removal of extracellular calcium. A similar transient elevation of [Ca2+](i) was elicited by EGF (100ngmL(-1)). The EGF receptor inhibitor, AG 1478 (30nM), and the MMP inhibitor, marimastat (100 nM), blocked the DHT-induced elevation of [Ca2+](i). %26lt;br%26gt;Conclusions and ImplicationsThese studies show that DHT elicits an androgen receptor-dependent acute elevation of [Ca2+](i) in HCPSC, most likely by activating EGF receptor signalling.

• 出版日期2013-10