Validation of Inhibitors of RhoGTPases for Cancer Treatment

现在有大量的证据表明，Ras相关的小分子Rho家族成员的异常激活， GTP酶在恶性肿瘤的增殖失控和侵袭性中起重要作用 细胞与Ras一样，Rho GTP酶作为调节开关控制多种信号通路 调节细胞增殖和存活、肌动蛋白组织和基因表达。因此，像激活 Ras的持续激活，Rho GTPases的持续激活可以显著促进异常生长， 人类恶性肿瘤的转移特性。然而，尽管Ras蛋白的直接突变激活 在30%的人类癌症中发现，迄今为止尚未发现Rho GTP酶。相反，Rho GTP酶 在人类癌症中通过多种间接机制被异常激活。例如，Racl是 在乳腺癌和结肠癌中通过选择性剪接和表达变体Raclb蛋白激活， 是组成性激活的，而RhoC表达增加与乳腺癌进展有关 和入侵。第三种机制涉及Rho鸟嘌呤核苷酸交换因子的异常激活 （RhoGEFs;也称为Dbl家族癌蛋白）。特别是Ras和G蛋白偶联受体 利用RhoGEFs介导生长转化和肿瘤细胞侵袭。Rho GTP酶反过来利用 ROCK丝氨酸/苏氨酸激酶促进肿瘤发生。同样，最近的研究表明， Ras相关蛋白（RalGEF）的另一个家族，Ral小GTP酶，作为Ras的重要介质 人类细胞的转化。Ral GTP酶的关键下游效应子是RalBPl，其是Rho GAP。 和Rho GTP酶的负调节因子。因此，Rho GTP酶及其调节子和效应子代表了 抗癌药物开发的重要目标。Rho和Ral GTP酶被修饰 通过牛儿基牛儿基转移酶I（GGTasel）进行后修饰，并且这种修饰是它们的 转换功能。我们提出了四个具体目标，以进一步评估Rho和Ral全球环境基金的作用， 它们在癌症发展中的GT3靶点，以及药理学抑制其功能的可行性 通过使用Rho GTP酶功能抑制剂（GGT酶I、RhoGEFs和ROCK抑制剂），用于癌症 治疗

There is now substantial evidence that aberrant activation of members of the Rho family of Ras-related small GTPases contributes significantly to the uncontrolled proliferation and invasive properties of malignant tumor cells. Like Ras, Rho GTPases function as regulated switches that control diverse signaling pathways regulating cell proliferation and survival, actin organization, and gene expression. Therefore, like activation of Ras, persistent activation of Rho GTPases can contribute significantly to the aberrant growth and metastatic properties of human malignancies. However, whereas direct mutational activation of Ras proteins is found in 30% of human cancers, this has not been found to date for Rho GTPases. Instead, Rho GTPases are aberrantly activated in human cancers by a diversity of indirect mechanisms. For example, Racl is activated in breast and colon cancers by alternative splicing and expression of the variant Raclb protein that is constitutively activated, whereas increased expression of RhoC is implicated in breast cancer progression and invasion. A third mechanism involves aberrant activation of Rho guanine nucleotide exchange factors (RhoGEFs; also called Dbl family oncoproteins). In particular, both Ras and G protein-coupled receptors utilize RhoGEFs to mediate growth transformation and tumor cell invasion. Rho GTPases in turn utilize the ROCK serine/threonine kinase to promote oncogenesis. Similarly, recent studies have implicated GEFs for another family of Ras-related proteins (RalGEFs), the Ral small GTPases, as important mediators of Ras transformation of human cells. A key downstream effector of Ral GTPases is RalBPl, which is a Rho GAP and a negative regulator of Rho GTPases. Thus, Rho GTPases and their regulators and effectors represent important targets for anti-cancer drug development. The Rho and Ral GTPases are modified posttranslationally by geranylgeranyltransferase I (GGTasel), and this modification is required for their transforming functions. We propose four specific aims to further evaluate the role of Rho and Ral GEFs and their GTPase targets in cancer development, and the feasibility of pharmacologic inhibition of their functions by using inhibitors of Rho GTPase function (inhibitors of GGTase I, RhoGEFs and ROCK), for cancer treatment.