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A novel androgen signalling pathway uses dihydrotestosterone, but not testosterone, to activate the EGF receptor signalling cascade in prostate stromal cells
Author(s) -
Oliver V L,
Poulios K,
Ventura S,
Haynes J M
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12307
Subject(s) - endocrinology , medicine , dihydrotestosterone , androgen receptor , inositol trisphosphate , biology , androgen , receptor , chemistry , inositol , hormone , prostate cancer , cancer
Background and Purpose Human 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 ([ Ca 2+ ] i ), has also been described in a number of cell types. In this study we investigate whether androgens acutely regulate [ Ca 2+ ] i in stromal cells derived from the human prostate. Experimental Approach Human‐cultured prostatic stromal cells ( HCPSC s) were loaded with the calcium‐sensitive fluorophore, fura‐2‐acetoxymethyl ester ( FURA ‐2 AM ) (10 μM). Changes in [ Ca 2+ ] i in response to the androgens, dihydrotestosterone ( DHT ) and testosterone, as well as EGF were measured by fluorescence microscopy. Key Results DHT , but not testosterone (0.03–300 nM), elicited concentration‐dependent elevations of [ Ca 2+ ] i within 1 min of addition. These responses were blocked by the androgen receptor antagonist, flutamide (10 μM); the sarcoplasmic reticulum ATP ase pump inhibitor, thapsigargin (1 μM); the inositol trisphosphate receptor inhibitor, 2‐aminoethyldiphenyl borate (50 μM) and the PLC inhibitor, U ‐73122 (1 μM). Responses were also blocked by the L‐type calcium channel blocker, nifedipine (1 μM), and by removal of extracellular calcium. A similar transient elevation of [ Ca 2+ ] i was elicited by EGF (100 ng·mL −1 ). The EGF receptor inhibitor, AG 1478 (30 nM), and the MMP inhibitor, marimastat (100 nM), blocked the DHT ‐induced elevation of [ Ca 2+ ] i . Conclusions and Implications These studies show that DHT elicits an androgen receptor‐dependent acute elevation of [ Ca 2+ ] i in HCPSC , most likely by activating EGF receptor signalling.