Like Cdc42 and Rac, high protein expression levels of the Rho GTPase RhoA appears to be selleck chemicals llc a frequent event in different types of human tumors, including colon cancer and increased RhoA activity correlates with poor prognosis and recurrence in hepatocellular carcinoma. Even though RhoA may be involved in colon cancer progression, our data reveal that RhoA is not suppressed by AZA197 treatment and thus is not a target for AZA197. Unlike RhoA, RhoB is often down regulated in human tumors and expression inversely cor relates with tumor aggressiveness. This can be explained by its potential role as a tumor suppressor and RhoB levels are attenuated commonly during malignant progression. In line with this, we did not detect active RhoB in control or AZA197 treated colon cancer cells, consist ent with the general aggressive Inhibitors,Modulators,Libraries behavior of these cells.

Cdc42 plays an important role in cytoskeleton organization and reducing Cdc42 activity with AZA197 resulted in a loss of filopodia formation and significantly reduced colon cancer cell cell migration and invasion capacity. Data from patients showing that Cdc42 is over expressed with high incidence in colorectal adenocarcin oma biopsies and the findings Inhibitors,Modulators,Libraries in this study, support the notion that Cdc42 inhibition could be used as a therapeutic strategy to fight colorectal cancer. This is supported by a report suggesting that active Cdc42 can enhance colorectal cancer cell migration and invasion. Furthermore, expression of constitutively active Cdc42 significantly increased filopodia formation and cell spread in colorectal cancer cells, which is in line with our findings.

Moreover, the finding that inhib ition of Cdc42 results in loss of elongated, mesenchymal morphology, which we also observed following AZA197 treatment, further strengthens the function Inhibitors,Modulators,Libraries of AZA197 as a Cdc42 inhibitor and the tumor promoting role of Cdc42 in colon cancer. However, activation of Cdc42 can induce cell adhesion and it has been recently shown that activated Cdc42 increases SW480 colorectal cancer cell adhesion, migration and invasion. It is therefore possible that AZA197 inhibition of Cdc42 also affects cell adhesion in addition to impair ment of colon cancer cell proliferation, migration and invasion. PAK1 is a main downstream effector of the Rho GTPases Rac1 and Cdc42. Overexpression of PAK1 has been detected in colorectal cancer and PAK1 expres sion closely correlated with the aggressive Inhibitors,Modulators,Libraries progression of colorectal cancer. A recent study Inhibitors,Modulators,Libraries showed that PAK1 dependent MAPK pathway activation selleck chemicals is required for colorectal cancer cell proliferation. PAK1 knockdown decreased proliferation and delayed the G1S cell cycle transition and increased apoptosis in vivo and in vitro.