Open AccessMetformin inhibits estrogen‐dependent endometrial cancer cell growth by activating the AMPK – FOXO 1 signal pathway
Author(s) -
Zou Jingfang,
Hong Liangli,
Luo Chaohuan,
Li Zhi,
Zhu Yuzhang,
Huang Tianliang,
Zhang Yongneng,
Yuan Huier,
Hu Yaqiu,
Wen Tengfei,
Zhuang Wanling,
Cai Bozhi,
Zhang Xin,
Huang Jiexiong,
Cheng Jidong
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13083
Subject(s) - metformin , ampk , biguanide , cell growth , downregulation and upregulation , endometrial cancer , amp activated protein kinase , protein kinase a , chemistry , phosphorylation , cancer research , endocrinology , pi3k/akt/mtor pathway , medicine , signal transduction , cancer , microbiology and biotechnology , biology , insulin , biochemistry , gene
Metformin is an oral biguanide commonly used for treating type II diabetes and has recently been reported to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study shows a marked loss of AMP ‐activated protein kinase ( AMPK ) phosphorylation and nuclear human Forkhead box O1 ( FOXO 1) protein in estrogen‐dependent endometrial cancer ( EC ) tumors compared to normal control endometrium. Metformin treatment suppressed EC cell growth in a time‐dependent manner in vitro ; this effect was cancelled by cotreatment with an AMPK inhibitor, compound C. Metformin decreased FOXO 1 phosphorylation and increased FOXO 1 nuclear localization in Ishikawa and HEC ‐1B cells, with non‐significant increase in FOXO 1 mRNA expression. Moreover, compound C blocked the metformin‐induced changes of FOXO 1 and its phosphorylation protein, suggesting that metformin upregulated FOXO 1 activity by AMPK activation. Similar results were obtained after treatment with insulin. In addition, transfection with si RNA for FOXO 1 cancelled metformin‐inhibited cell growth, indicating that FOXO 1 mediated metformin to inhibit EC cell proliferation. A xenograft mouse model further revealed that metformin suppressed HEC ‐1B tumor growth, accompanied by downregulated ki‐67 and upregulated AMPK phosphorylation and nuclear FOXO 1 protein. Taken together, these data provide a novel mechanism of antineoplastic effect for metformin through the regulation of FOXO 1, and suggest that the AMPK – FOXO 1 pathway may be a therapeutic target to the development of new antineoplastic drugs.