Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer.
Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer.
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DOI：
10.1038/bjc.2014.99
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发表时间：
2014-04-15
影响因子：
8.8
通讯作者：
Clarke, N. W.
中科院分区：
文献类型：
--
作者：
Brown, M.;Roulson, J-A;Hart, C. A.;Tawadros, T.;Clarke, N. W.
前列腺癌 (CaP) 骨转移会导致与 CaP 相关的发病率/死亡率。 omega-6 多不饱和脂肪酸 (PUFA) 花生四烯酸 (AA) 和亲脂性他汀类药物影响 CaP 细胞的转移样行为，调节 CaP 迁移到骨髓基质的关键转移步骤。使用 AA 刺激和/或辛伐他汀 (SIM) 治疗，对 CaP 细胞通过骨髓内皮细胞 (BMEC) 的粘附和侵袭进行显微镜分析和测量。通过蛋白质印迹和 Rho 测定分析 PC-3、PC3-GFP 和 DU-145 的变形虫特征。 CaP 细胞系 PC-3、PC3-GFP 和 DU-145 具有跨 BMEC 层迁移的能力。特异性阿米巴样抑制可减少跨内皮迁移 (TEM)。 AA 在 Rho 信号驱动下刺激变形虫特征。选择性敲除 Rho 通路成分（RhoA、RhoC、Rho 相关蛋白激酶 1 (ROCK1) 和 ROCK2）表明 Rho 信号传导对于 TEM 至关重要。分析了这些成分的功能，包括对 BMEC 的粘附、2D 迁移以及 AA 对变形虫表型的诱导。 PC3-GFP 和 DU-145 的 SIM 处理可降低 TEM，从而抑制 Rho 通路信号传导。 AA 诱导的 TEM 是通过 Rho 驱动的变形虫表型的诱导介导的。抑制这种细胞迁移过程可能是高危 CaP 的重要治疗靶点。
Bone metastases in prostate cancer (CaP) result in CaP-related morbidity/mortality. The omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) and lipophilic statins affect metastasis-like behaviour in CaP cells, regulating the critical metastatic step of CaP migration to the bone marrow stroma. Microscopic analysis and measurement of adhesion and invasion of CaP cells through bone marrow endothelial cells (BMEC) was undertaken with AA stimulation and/or simvastatin (SIM) treatment. Amoeboid characteristics of PC-3, PC3-GFP and DU-145 were analysed by western blotting and Rho assays. The CaP cell lines PC-3, PC3-GFP and DU-145 share the ability to migrate across a BMEC layer. Specific amoeboid inhibition decreased transendothelial migration (TEM). AA stimulates amoeboid characteristics, driven by Rho signalling. Selective knock-down of components of the Rho pathway (RhoA, RhoC, Rho-associated protein kinase 1 (ROCK1) and ROCK2) showed that Rho signalling is crucial to TEM. Functions of these components were analysed, regarding adhesion to BMEC, migration in 2D and the induction of the amoeboid phenotype by AA. TEM was reduced by SIM treatment of PC3-GFP and DU-145, which inhibited Rho pathway signalling. AA-induced TEM is mediated by the induction of a Rho-driven amoeboid phenotype. Inhibition of this cell migratory process may be an important therapeutic target in high-risk CaP.
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