Nonetheless, 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 can be hence feasible that AZA197 inhibition of Cdc42 also impacts cell adhesion as well as impair ment of colon cancer cell proliferation, migration and invasion. PAK1 is a principal downstream effector with the 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 current study showed that PAK1 dependent MAPK pathway activation is necessary for colorectal cancer cell proliferation. PAK1 knockdown decreased proliferation and delayed the G1 S cell cycle transition and increased apoptosis in vivo and in vitro.
In line with these findings, we observed substantial down regulation in the activation of PAK1 and ERK linked with decreased proliferation following AZA197 therapy in SW620 cancer cells in vitro and in SW620 cancer tissue. On top of that, Cdc42 selleck chemical inhibition by AZA197 resulted in improved apoptosis in vivo and in vitro. Additional over, colon cancer cells overexpressing PAK1 have larger migration prices, whereas down regulation of PAK1 signifi cantly reduces cell migration. That is in line with our findings of reduced SW620 cancer cell migration follow ing AZA197 therapy. Furthermore, the ERK dependent pathway is necessary in PAK1 mediated colon cancer cell migration and invasion. Consequently, the observed down regulation in the Cdc42 PAK1 signaling pathway could consequently constitute the main effector pathway of AZA197 in colon cancer.
On the other hand, there are some limitations towards the interpret ation from the possible effects of AZA197 on cell prolifer ation and cancer cell migration and invasion within this study. Our information in SW620 Nutlin-3b ic50 cells suggest that AZA197 could impact cancer cell viability at concentrations that inhibit Cdc42, cell proliferation and actin cytoskeletal modifications in SW620 cells. Impaired cell viability may possibly be anticipated since in addition to regulation of cell migra tion and invasion, Cdc42 and also the downstream signaling mediator PAK1 have also been implicated in regulation from 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 impacted by AZA197 at concentrations that drastically inhibit Cdc42 activity as well as cancer cell migration and invasion. In addition, at concentrations that inhibit Cdc42 mediated mor phological alterations, we usually do not see significant effects of AZA197 on cell viability in HT 29 cells.