Wang Yiming, Gratzke Christian, Tamalunas Alexander, Rutz Beata, Ciotkowska Anna, Strittmatter Frank, Herlemann Annika, Janich Sophie, Waidelich Raphaela, Liu Chunxiao, Stief Christian G, Hennenberg Martin
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Br J Pharmacol. 2016 Dec;173(23):3342-3358. doi: 10.1111/bph.13623. Epub 2016 Nov 1.
In benign prostatic hyperplasia, increased prostate smooth muscle tone and prostate volume may contribute alone or together to urethral obstruction and voiding symptoms. Consequently, it is assumed there is a connection between smooth muscle tone and growth in the prostate, but any molecular basis for this is poorly understood. Here, we examined effects of Src family kinase (SFK) inhibitors on prostate contraction and growth of stromal cells.
SFK inhibitors, AZM475271 and PP2, were applied to human prostate tissues to assess effects on smooth muscle contraction, and to cultured stromal (WPMY-1) and c-Src-deficient cells to examine effects on proliferation, actin organization and viability.
SFKs were detected by real time PCR, western blot and immunofluorescence in human prostate tissues, some being located to smooth muscle cells. AZM475271 (10 μM) and PP2 (10 μM) inhibited SFK in prostate tissues and WPMY-1 cells. Both inhibitors reduced α -adrenoceptor-mediated and neurogenic contraction of prostate strips. This may result from cytoskeletal deorganization, which was observed in response to AZM475271 and PP2 in WPMY-1 cells by staining of actin filaments with phalloidin. This was paralleled by reduced proliferation of wildtype but not of c-Src-deficient cells; cytotoxicity was mainly observed at higher concentrations (>50 μM).
In human prostate, smooth muscle tone and growth are both controlled by an SFK-dependent process, which may explain their common role in bladder outlet obstruction. Targeting prostate smooth muscle tone and prostate growth simultaneously by a single compound may, in principal, be possible.
在良性前列腺增生中，前列腺平滑肌张力增加和前列腺体积增大可能单独或共同导致尿道梗阻和排尿症状。因此，人们认为平滑肌张力与前列腺生长之间存在联系，但对此的任何分子基础都知之甚少。在此，我们研究了Src家族激酶（SFK）抑制剂对前列腺收缩和基质细胞生长的影响。
将SFK抑制剂AZM475271和PP2应用于人类前列腺组织，以评估对平滑肌收缩的影响，并应用于培养的基质（WPMY-1）细胞和c-Src缺陷细胞，以研究对增殖、肌动蛋白组织和活力的影响。
通过实时PCR、蛋白质印迹和免疫荧光在人类前列腺组织中检测到SFK，其中一些定位于平滑肌细胞。AZM475271（10μM）和PP2（10μM）抑制前列腺组织和WPMY-1细胞中的SFK。两种抑制剂均降低了α-肾上腺素能受体介导的和神经源性的前列腺条带收缩。这可能是由于细胞骨架解聚所致，通过用鬼笔环肽对肌动蛋白丝进行染色，在WPMY-1细胞中观察到AZM475271和PP2可引起这种情况。与此同时，野生型细胞而非c-Src缺陷细胞的增殖减少；细胞毒性主要在较高浓度（>50μM）时观察到。
在人类前列腺中，平滑肌张力和生长均受SFK依赖性过程的控制，这可能解释了它们在膀胱出口梗阻中的共同作用。原则上，用单一化合物同时靶向前列腺平滑肌张力和前列腺生长可能是可行的。
