Smooth muscle contraction and growth of stromal cells in the human prostate are both inhibited by the Src family kinase inhibitors, AZM475271 and PP2
Smooth muscle contraction and growth of stromal cells in the human prostate are both inhibited by the Src family kinase inhibitors, AZM475271 and PP2
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人类前列腺中的平滑肌收缩和基质细胞生长均受到 Src 家族激酶抑制剂 AZM475271 和 PP2 的抑制
DOI：
10.1111/bph.13623
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发表时间：
2016
影响因子：
7.3
通讯作者：
Hennenberg M
中科院分区：
文献类型：
--
作者：
Wang Y;Gratzke C;Tamalunas A;Rutz B;Ciotkowska A;Strittmatter F;Herlemann A;Janich S;Waidelich R;Stief CG;Hennenberg M
背景和目的在良性前列腺增生症中，前列腺平滑肌张力和前列腺体积的增加可能单独或共同导致尿路梗阻和排尿症状。因此，人们认为在前列腺的平滑肌张力和生长之间存在联系，但对此的任何分子基础都知之甚少。在这里，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。实验方法将SFK抑制剂AZM475271和PP2应用于人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细胞(WPMY-1)和c-Src缺陷细胞以检测其对增殖、肌动蛋白组织和存活率的影响。AZM475271(10μM)和PP2(10μM)对前列腺组织和WPMY-1细胞的SFK有抑制作用。这两种抑制剂都减少了α1肾上腺素受体介导的前列腺条的神经源性收缩。这可能是由于细胞骨架的破坏，对AZM475271和PP2的反应，用鬼臼毒素染色观察到WPMY-1细胞中的肌动蛋白细丝。与此平行的是野生型细胞的增殖减少，但c-src缺陷细胞的增殖减少；细胞毒性主要在较高浓度(>；50μM)观察到。结论和暗示在人类前列腺中，平滑肌张力和生长都受sfk依赖的过程控制，这可能解释了它们在膀胱出口梗阻中的共同作用。原则上，通过一种化合物同时靶向前列腺肌张力和前列腺生长是可能的。
Background and PurposeIn 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.Experimental ApproachSFK 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.Key ResultsSFKs 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 α1‐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).Conclusions and ImplicationsIn 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.
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DOI：
10.1007/s11918-007-0003-x
发表时间：
2007
期刊：
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作者：
M. Phillippe;L. Sweet;Diana F. Bradley;D. Engle
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影响因子：
7.3
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