G12 signaling through c-Jun NH2-terminal kinase promotes breast cancer cell invasion.
G12 signaling through c-Jun NH2-terminal kinase promotes breast cancer cell invasion.
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DOI：
10.1371/journal.pone.0026085
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Casey PJ
中科院分区：
文献类型：
--
作者：
Juneja J;Cushman I;Casey PJ
通过异源三聚体G蛋白G12经由Rho的信号传导诱导乳腺癌细胞侵袭的显著增加。在这项研究中，提供的证据表明，c-Jun NH 2-末端激酶（JNK）是G12在该途径上的关键下游效应子。组成型活性Gα12的表达或凝血酶对G12信号的激活导致JNK和c-Jun磷酸化增加。药理学抑制JNK或敲低JNK表达的siRNA显着降低G12诱导的JNK激活以及乳腺癌细胞侵入重建基底膜的能力。此外，显性负性Rho的表达或用Rho激酶抑制剂ROCK处理细胞减少G12诱导的JNK和c-Jun活化，并且ROCK抑制剂处理也抑制G12诱导的细胞侵袭。JNK敲低或ROCK抑制剂处理对G12激活Rho没有影响。两者合计，我们的数据表明，JNK激活所需的G12诱导的乳腺癌细胞的侵袭和JNK是下游的Rho和ROCK在这一途径。这项研究暗示了G12刺激的丝裂原活化蛋白激酶级联在癌细胞侵袭中的作用，并支持JNK在癌症进展中的作用。
Signaling through the heterotrimeric G protein, G12, via Rho induces a striking increase in breast cancer cell invasion. In this study, evidence is provided that the c-Jun NH2-terminal kinase (JNK) is a key downstream effector of G12 on this pathway. Expression of constitutively-active Gα12 or activation of G12 signaling by thrombin leads to increased JNK and c-Jun phosphorylation. Pharmacologic inhibition of JNK or knockdown of JNK expression by siRNA significantly decreases G12-induced JNK activation as well as the ability of breast cancer cells to invade a reconstituted basement membrane. Furthermore, expression of dominant-negative Rho or treatment of cells with an inhibitor of the Rho kinase, ROCK, reduces G12-induced JNK and c-Jun activation, and ROCK inhibitor treatment also inhibits G12-induced cellular invasion. JNK knockdown or ROCK inhibitor treatment has no effect on activation of Rho by G12. Taken together, our data indicate that JNK activation is required for G12-induced invasion of breast cancer cells and that JNK is downstream of Rho and ROCK on this pathway. This study implicates a G12-stimulated mitogen-activated protein kinase cascade in cancer cell invasion, and supports a role for JNK in cancer progression.