Validation of Inhibitors of RhoGTPases for Cancer Treatment

点击翻译按钮获取中文摘要

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.