Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context.
Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context.
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Rho激酶（岩石）信号传导的抑制剂在3D背景下恢复了乳腺癌细胞的恶性表型。
DOI：
10.18632/oncotarget.9395
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发表时间：
2016-05-31
期刊：
影响因子：
--
通讯作者：
Bissell MJ
中科院分区：
文献类型：
--
作者：
Matsubara M;Bissell MJ
极性和静止的丧失以及细胞侵袭性的增加与乳腺肿瘤的进展有关。 ROCK 在肌动蛋白细胞骨架重排中起着核心作用。我们使用富含层粘连蛋白的细胞外基质制成的凝胶中的非恶性细胞和癌细胞的生理相关 3D 培养物来研究 ROCK 功能。尽管与非恶性细胞相比，癌细胞中 ROCK1 和 ROCK2 的表达水平升高，但在 2D 培养物中并未观察到这种情况。恶性细胞显示 MLC 磷酸化增加，对应于紊乱的 F-肌动蛋白。 ROCK 信号传导的抑制可恢复极性，减少 F-肌动蛋白的混乱，并导致增殖减少。抑制 ROCK 还降低 EGFR 和 Integrinβ1 水平，从而抑制 Akt、MAPK 和 FAK 的激活以及 GLUT3 和 LDHA 水平。同样，ROCK 抑制不会在 2D 中抑制这些分子。缺乏 E-钙粘蛋白的三阴性乳腺癌细胞系具有高水平的 ROCK，但对 ROCK 抑制剂的敏感性较低。然而，E-钙粘蛋白的外源过度表达使得这些细胞对 ROCK 抑制极其敏感。我们的研究结果丰富了越来越多的文献，证明背景和组织结构不仅在决定正常和恶性表型的调节方面，而且在决定药物反应方面的重要性。
Loss of polarity and quiescence along with increased cellular invasiveness are associated with breast tumor progression. ROCK plays a central role in actin-cytoskeletal rearrangement. We used physiologically relevant 3D cultures of nonmalignant and cancer cells in gels made of laminin-rich extracellular matrix, to investigate ROCK function. Whereas expression levels of ROCK1 and ROCK2 were elevated in cancer cells compared to nonmalignant cells, this was not observed in 2D cultures. Malignant cells showed increased phosphorylation of MLC, corresponding to disorganized F-actin. Inhibition of ROCK signaling restored polarity, decreased disorganization of F-actin, and led to reduction of proliferation. Inhibition of ROCK also decreased EGFR and Integrinβ1 levels, and consequently suppressed activation of Akt, MAPK and FAK as well as GLUT3 and LDHA levels. Again, ROCK inhibition did not inhibit these molecules in 2D. A triple negative breast cancer cell line, which lacks E-cadherin, had high levels of ROCK but was less sensitive to ROCK inhibitors. Exogenous overexpression of E-cadherin, however, rendered these cells strikingly sensitive to ROCK inhibition. Our results add to the growing literature that demonstrate the importance of context and tissue architecture in determining not only regulation of normal and malignant phenotypes but also drug response.
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影响因子：
11.2
作者：
Fournier MV;Fata JE;Martin KJ;Yaswen P;Bissell MJ
通讯作者：
Bissell MJ
影响因子：
4.5
作者：
Kamai, T;Arai, K;Yoshida, K
通讯作者：
Yoshida, K
DOI：
10.1186/bcr2938
发表时间：
2012-01-19
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dave B;Mittal V;Tan NM;Chang JC
通讯作者：
Chang JC
影响因子：
3.5
作者：
Ishizaki, T;Naito, M;Narumiya, S
通讯作者：
Narumiya, S
影响因子：
4.5
作者：
Kamai, T;Kawakami, S;Yoshida, KI
通讯作者：
Yoshida, KI