title: Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway.
abstract: 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-RARα 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.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Huai
authors.forename: Cuicui
authors.initials: C
authors.lastname: Wang
authors.forename: Cuiping
authors.initials: C
authors.lastname: Zhang
authors.forename: Qihui
authors.initials: Q
authors.lastname: Li
authors.forename: Yirui
authors.initials: Y
authors.lastname: Chen
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Jia
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xing
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tian
authors.forename: Qing
authors.initials: Q
authors.lastname: Rao
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D008687:Metformin