Diallyl disulfide induces downregulation and inactivation of cofilin1 differentiation via the Rac1/ROCK1/LIMK1 pathway in leukemia cells.

Abstract

Cofilin is associated with cell differentiation; however, to the best of our knowledge, no data have indicated an association between the cofilin 1 pathway and leukemia cell differentiation. The present study investigated the involvement of the cofilin 1 signaling pathway in diallyl disulfide (DADS)-induced differentiation and the inhibitory effects on the proliferation, migration, and invasion of human leukemia HL-60 cells. First, it was identified that 8 µM DADS suppressed cell proliferation, migration and invasion, and induced differentiation based on the reduced nitroblue tetrazolium ability and increased CD11b and CD33 expression. DADS significantly downregulated the expression of cofilin 1 and phosphorylated cofilin 1 in HL-60 leukemia cells. Second, it was verified that silencing cofilin 1 markedly promoted 8 µM DADS-induced differentiation and the inhibitory effect on cell proliferation and invasion. Overexpression of cofilin 1 obviously suppressed 8 µM DADS-induced differentiation and the inhibitory effect on cell proliferation and invasion. Third, the present study examined the mechanisms by which 8 µM DADS decreases cofilin 1 expression and activation. The results revealed that 8 µM DADS inhibited the mRNA and protein expression of Rac1, Rho-associated protein kinase 1 (ROCK1) and LIM domain kinase 1 (LIMK1) as well as the phosphorylation of LIMK1 in HL-60 cells, while 8 µM DADS enhanced the effects of the Rac1-ROCK1-LIMK1 pathway in cells overexpressing cofilin 1 compared with that in control HL-60 cells. These results suggest that the anticancer function of DADS on HL-60 leukemia cells is regulated by the Rac1-ROCK1-LIMK1-cofilin 1 pathway, indicating that DADS could be a promising anti-leukemia therapeutic compound.