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Analysis of activation mechanisms of Rho and RhoGEFs as a new molecular target for lung cancer therapy.

分析 Rho 和 RhoGEFs 作为肺癌治疗新分子靶点的激活机制。

基本信息

批准号：
15590811
负责人：
CHIKUMI Hiroki
金额：
$ 1.15万
依托单位：
Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590811/
关键词：
Rho RhoGEF lung cancer PDZ-RhoGEF p115RhoGEF LARG RDZ-RhoGEF Pho

项目摘要

Rho GTPases play an essential role in the control of various cellular functions. Accumulating evidence suggests that RhoA overexpression contributes to human cancer development. However, the activation states of RhoA are poorly defined in cancer cells. In this study, we examined both the expression levels and the activation states of RhoA and its upstream activator, RhoGEFs, in various lung cancer cells. Additionally, we analyzed the mechanisms of RhoA activation in these cells to search for new molecular targets for lung cancer treatment. We found that RhoA is activated in various lung cancer cells independent of its expression levels. Especially, the activation status of RhoA is higher comparing to its expression levels in small cell lung cancer (SCLC) cells. Next, we measured the expression levels of three RGL-domain containing RhoGEFs: p115RhoGEF, LARG, and PDZ-RhoGEF, as a candidate for direct activator of RhoA in these cancer cells for the first time. We found that LARG is strongly expressed in all types of lung cancer cells, suggesting the importance of LARG in lung cancer pathogenesis. Finally, we dissected the signaling pathway from cell surface receptor to Rho in SCLC cells using broad-spectrum GPCR antagonist and recently reported Gαq-selective inhibitor. We found that the high activation state of RhoA in SCLC cells mainly depends on a neuroendocrine peptide autocrine system which signals through Gα12 coupled GPCR to RhoA. These results suggest that inhibition of this signaling pathway will be the possible new strategies for targeted lung cancer therapy.

Rho GTP酶在控制各种细胞功能中起重要作用。越来越多的证据表明，RhoA过度表达有助于人类癌症的发展。然而，RhoA的激活状态在癌细胞中定义不清。在这项研究中，我们研究了RhoA及其上游激活因子RhoGEFs在各种肺癌细胞中的表达水平和激活状态。此外，我们分析了这些细胞中RhoA激活的机制，以寻找新的肺癌治疗分子靶点。我们发现RhoA在各种肺癌细胞中被激活，与其表达水平无关。特别地，RhoA的活化状态与其在小细胞肺癌（SCLC）细胞中的表达水平相比更高。接下来，我们测量了三种含有RGL结构域的RhoGEFs的表达水平：p115 RhoGEF，LARG和PDZ-RhoGEF，作为RhoA在这些癌细胞中的直接激活剂的候选者。我们发现LARG在所有类型的肺癌细胞中均强烈表达，这表明LARG在肺癌发病机制中的重要性。最后，我们利用广谱GPCR拮抗剂和最近报道的Gα q选择性抑制剂，分析了SCLC细胞表面受体到Rho的信号通路。我们发现，小细胞肺癌细胞中RhoA的高活化状态主要依赖于神经内分泌肽自分泌系统，该系统通过Gα12偶联GPCR向RhoA发出信号。这些结果表明，抑制该信号通路将成为肺癌靶向治疗的新策略。