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

Huachao Zhu, Xiaoyan Zheng, Hui Feng, Wenjuan Wang, Xiaoning Wang, Miaojing Li, Huaiyu Wang, Jing Zhao, Pengcheng He

Molecular medicine reports 2020 Dec

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All‑trans retinoic acid (ATRA) and arsenic trioxide (As2O3) 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 As2O3, 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 As2O3‑induced apoptosis in NB4‑R1 cells were further investigated. The results revealed that cell viability was markedly suppressed and apoptosis was increased in the As2O3‑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 As2O3‑treated group compared with the control. Western blotting further revealed that As2O3 treatment decreased the cytoplasmic cofilin‑1 level but increased its expression in the mitochondrion. However, the opposite effects of As2O3 on the cytochrome C distribution were found in NB4‑R1 cells. This suggested that As2O3 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 As2O3‑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 As2O3‑treated NB4‑R1 cells. In conclusion, cofilin‑1 played a role in As2O3‑induced NB4‑R1 cell apoptosis and it might be a novel target for APL treatment.

Citation

Huachao Zhu, Xiaoyan Zheng, Hui Feng, Wenjuan Wang, Xiaoning Wang, Miaojing Li, Huaiyu Wang, Jing Zhao, Pengcheng He. Role of cofilin‑1 in arsenic trioxide‑induced apoptosis of NB4‑R1 cells. Molecular medicine reports. 2020 Dec;22(6):4645-4654