Abstract
Benign prostatic hyperplasia (BPH) is a progressive urological disorder related to an imbalance between cell proliferation and apoptosis. BPH is characterized by an increased number of epithelial, smooth muscle and stromal cells. Prostatic enlargement contributes to the lower urinary tract symptoms (LUTS/BPH). The participation of epidermal growth factor (EGF) receptor in G protein‐coupled receptor signaling is a process of transactivation critical for mitogenic activity in some models. Here we focused on the putative role of EGF receptor transactivation mediated by α1D‐adrenoceptors in stromal cell growth. Human BPH cells were treated with phenylephrine (3 μM) or vehicle (control) for either 15 min or 48h, and cell growth and protein expression were examined by Trypan Blue exclusion/MTT and Western blotting assays, respectively. Cell treatment with 3 μM phenylephrine (48h) induced a cell growth effect comparable to 0.1 μM EGF (166.3 ± 13.7 and 157.4 ± 14%, n = 5 experiments performed in quadruplicate, for phenylephrine and EGF, respectively, P < 0.001). The effect of phenylephrine was blocked by the α1D‐adrenoceptor antagonists BMY7378 (50 nM; 92.8 ± 4.7%, n = 5, P < 0.001), LDT3 (50 nM; 94.2 ± 8.2%, n = 5, P < 0.001) and LDT5 (50 nM; 92.6 ± 9.1%, n = 5, P < 0.001) suggesting that these receptors are involved in cell growth. Then we evaluated the downstream α1D‐adrenoceptor signaling. Phenylephrine (3 μM, 15 min) induced p‐ERK expression and the α1D‐adrenoceptor antagonists also blocked this effect (n = 4). Furthermore, the phenylephrine‐induced cell growth was blocked by the metalloproteinase inhibitor GM6001 (10 μM), the selective EGF receptor inhibitor AG1478 (5 μM) and MEK inhibitor PD98059 (1 μM). In conclusion, these results suggest that EGF receptor transactivation by α1D‐adrenoceptor is relevant for human stromal cell proliferation and may contribute to prostatic enlargement and LUTS/BPH.Support or Funding InformationCNPq, Brazil [455436/2014‐2]
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