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.