Role of cofilin-1 in arsenic trioxide-induced apoptosis of NB4-R1 cells

All-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) are currently first-line treatments for acute promyelocytic leukemia (APL). However, a number of patients with APL are resistant to ATRA but still sensitive to As(2)O(3), and the underlying mechanisms of this remain unclear. In the present study, two-dimensional gel electrophoresis, mass spectrometry and other proteomic methods were applied to screen and identify the differentially expressed proteins between the retinoic acid-sensitive cell lines and drug-resistant cell lines. The results demonstrated that in retinoic acid-resistant NB4-R1 cells, the protein expression of cofilin-1 was markedly increased compared with that in the drug-sensitive NB4 cells. Subsequently, the effects of cofilin-1 on As(2)O(3)-induced apoptosis in NB4-R1 cells were further investigated. The results revealed that cell viability was markedly suppressed and apoptosis was increased in the As(2)O(3)-treated NB4-R1 cells, with increased expression levels of cleaved-poly (ADP-ribose) polymerase and cleaved-caspase 12. Cofilin-1 expression was significantly decreased at both the mRNA and protein levels in the As(2)O(3)-treated group compared with the control. Western blotting further revealed that As(2)O(3) treatment decreased the cytoplasmic cofilin-1 level but increased its expression in the mitochondrion. However, the opposite effects of As(2)O(3) on the cytochrome C distribution were found in NB4-R1 cells. This suggested that As(2)O(3) can induce the transfer of cofilin-1 from the cytoplasm to mitochondria and trigger the release of mitochondrial cytochrome C in NB4-R1 cells. Moreover, cofilin-1 knockdown by its specific short hairpin RNA significantly suppressed As(2)O(3)-induced NB4-R1 cell apoptosis and inhibited the release of mitochondrial cytochrome C. Whereas, overexpression of cofilin-1 using a plasmid vector carrying cofilin-1 increased the release of cytochrome C into the cytoplasm from the mitochondria in As(2)O(3)-treated NB4-R1 cells. In conclusion, cofilin-1 played a role in As(2)O(3)-induced NB4-R1 cell apoptosis and it might be a novel target for APL treatment.