Overexpression of CDC42SE1 in A431 Cells Reduced Cell Proliferation by Inhibiting the Akt Pathway

Cell division cycle 42 (CDC42), a small Rho GTPase, plays a critical role in many cellular processes, including cell proliferation and survival. CDC42 interacts with the CRIB (Cdc42- and Rac-interactive binding) domain of CDC42SE1, a small effector protein of 9 kDa. We found that the expression of CDC42SE1 was reduced in human skin cancer samples relative to matched perilesional control. Exogenous expression of CDC42SE1 but not CDC42SE1^H38A (mutation within CRIB domain) in A431 cells (A431^SE1, A431^SE1-H38A) reduced cell proliferation. Antibody microarray analysis of A431^Ctrl and A431^SE1 lysate suggested that reduced A431^SE1 cells proliferation was due to inhibition of Akt pathway, which was confirmed by the reduced P-Akt and P-mTOR levels in A431^SE1 cells compared to A431^Ctrl cells. This suggests that CDC42SE1 modulates the CDC42-mediated Akt pathway by competing with other effector proteins to bind CDC42. A431^SE1 cells formed smaller colonies in soft agar compared to A431^Ctrl and A431^SE1-H38A cells. These findings correlate with nude mice xenograft assays, where A431^SE1 cells formed tumors with significantly-reduced volume compared to the tumors formed by A431^Ctrl cells. Our results suggest that CDC42SE1 is downregulated in skin cancer to promote tumorigenesis, and thus CDC42SE1 might be an important marker of skin cancer progression.