Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway
- 作者：Lei Huai ; Cuicui Wang ; Cuiping Zhang ; Qihui Li ; Yirui Chen ; Yujiao Jia ; Yan Li ; Haiyan Xing ; Zheng Tian ; Qing Rao ; Min Wang ; Jianxiang Wang ; wangjx@ihcams.ac.cn
- 关键词：Metformin ; Acute promyelocytic leukemia (APL) ; Apoptosis ; Differentiation ; Signaling pathway
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2012
- 期刊代码：159_0006291x
- 类别：bio
- 出版时间：8 June, 2012
- 卷：422
- 期：3
- 页码：398-404
- 文件大小：1038 K
摘要
Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR伪 and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.