On the other hand, 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 truly is as a result possible that AZA197 inhibition of Cdc42 also impacts cell adhesion as well as impair ment of colon cancer cell proliferation, migration and invasion. PAK1 is really a key downstream effector of your Rho GTPases Rac1 and Cdc42. Overexpression of PAK1 has been detected in colorectal cancer and PAK1 expres sion closely correlated with the aggressive progression of colorectal cancer. A recent study showed that PAK1 dependent MAPK pathway activation is essential for colorectal cancer cell proliferation. PAK1 knockdown decreased proliferation and delayed the G1 S cell cycle transition and enhanced apoptosis in vivo and in vitro.
In line with these findings, we observed important down regulation in the activation of PAK1 and ERK associated with decreased proliferation following AZA197 therapy in SW620 cancer cells in vitro and in SW620 cancer tissue. Furthermore, Cdc42 the full details inhibition by AZA197 resulted in enhanced apoptosis in vivo and in vitro. Far more more than, colon cancer cells overexpressing PAK1 have greater migration prices, whereas down regulation of PAK1 signifi cantly reduces cell migration. This is in line with our findings of lowered SW620 cancer cell migration comply with ing AZA197 remedy. Furthermore, the ERK dependent pathway is required in PAK1 mediated colon cancer cell migration and invasion. Consequently, the observed down regulation on the Cdc42 PAK1 signaling pathway could therefore constitute the main effector pathway of AZA197 in colon cancer.
Nevertheless, you will find some limitations towards the interpret ation with the potential effects of AZA197 on cell prolifer ation and cancer cell migration and invasion in this study. Our data in SW620 more bonuses cells suggest that AZA197 may perhaps effect cancer cell viability at concentrations that inhibit Cdc42, cell proliferation and actin cytoskeletal modifications in SW620 cells. Impaired cell viability could be expected since along with regulation of cell migra tion and invasion, Cdc42 along with the downstream signaling mediator PAK1 have also been implicated in regulation in the cell cycle, thereby affecting cell survival and apoptosis, which is in line with our findings in SW620 cells. In contrast, in HT 29 cancer cells, viability and proliferation were not affected by AZA197 at concentrations that significantly inhibit Cdc42 activity also as cancer cell migration and invasion. Additionally, at concentrations that inhibit Cdc42 mediated mor phological alterations, we do not see considerable effects of AZA197 on cell viability in HT 29 cells.