Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPK alpha
文献类型：期刊论文
| 作者 | Yan, Min1,2; Qi, Huan1; Xia, Tian1; Zhao, Xinjie1; Wang, Wen1,2; Wang, Zhichao1,2; Lu, Chang1,3; Ning, Zhen1,3; Chen, Huan1,2; Li, Tongming1 |
| 刊名 | METABOLISM-CLINICAL AND EXPERIMENTAL
 |
| 出版日期 | 2019-02-01 |
| 卷号 | 91页码:18-29 |
| 关键词 | Metformin Ampk Metabolomics Metabolic flux Independence |
| ISSN号 | 0026-0495 |
| DOI | 10.1016/j.metabol.2018.11.010 |
| 通讯作者 | Xu, Guowang(xugw@dicp.ac.cn) ; Piao, Hai-long(hpiao@dicp.ac.cn) |
| 英文摘要 | Background: Metformin is a first-line drug for treating type 2 diabetes and has gained considerable interest as a potential anticancer agent. Increasing evidence suggests that metformin antagonizes diabetes and tumors through disrupting metabolic homeostasis and altering energy state. However, whether AMP activated protein kinase (AMPK) contributes to such effects of metformin remains controversial. Methods: We performed integrative metabolomics analyses to systematically examine the effects of metformin on metabolic pathways in Prkaa1 wild type (WT) and knock-out (KO) mouse embryonic fibroblast (MEF) cells as well as human cells based on gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry (CE-MS). Results: Metformin treatment induced metabolic reprogramming and reduced the energy state of both Prkaa1 WT and KO MEF cells, as evidenced by suppressed tricarboxylic acid (TCA) cycle, elevated lactate production as well as decreased NAD(+)/NADH ratio. Additionally, metabolic flux analysis also showed that metformin Ampk alpha-independently increased metabolic flux from glucose to lactate and decreased metabolic flux from acetyl-CoA to TCA cycle as well as from pyruvate to malate. Moreover, metformin Ampk alpha-dependently upregulated P-Acc but Ampk alpha-independently inhibited the levels of P-mTor, P-S6, Lc3,Atgl and P-Erk in MEF cells. Similarly, we demonstrated that a commonly used AMPK agonist 5-Aminoimidazolc-4-carboxamidc ribonudeotide (AICAR) and fetal bovine serum (FBS) starvation, as a common model for energy stress, both led to Ampk alpha-independent metabolism alterations in MEF cells. Furthermore, these effects of metformin were also confirmed in human hepatocellular carcinoma (HCC) cells as well as in MCF10A shControl and shPRKAA1 cells. Importantly, we found that metformin could obviously inhibit colony conformation of HCC cells in an Ampk alpha-independent manner. Conclusions: Our data highlight a comprehensive view of metabolic reprogramming mediated by metformin as well as AICAR. These observations suggest that metformin could affect cellular metabolism largely bypassing Ampk alpha, and may provide a new insight for its dinical usage. (C) 2018 Elsevier Inc. All rights reserved. |
| WOS关键词 | ACTIVATED PROTEIN-KINASE ; CELL-CYCLE ARREST ; CLINICAL-OUTCOMES ; CANCER CELLS ; GROWTH ; AICAR ; COMPLEX ; INHIBITION ; MECHANISM ; PATHWAY |
| 资助项目 | National Key Research and Development Program of China[2016YFC0903302] ; National Natural Science Foundation of China[81672440] ; Innovation program of science and research from the DICP, CAS[DICP TMSR201601] ; 100 Talents Program of Chinese Academy of Sciences |
| WOS研究方向 | Endocrinology & Metabolism |
| 语种 | 英语 |
| WOS记录号 | WOS:000470301900003 |
| 出版者 | W B SAUNDERS CO-ELSEVIER INC |
| 资助机构 | National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences |
| 源URL | [http://cas-ir.dicp.ac.cn/handle/321008/172014]  |
| 专题 | 大连化学物理研究所_中国科学院大连化学物理研究所 |
| 通讯作者 | Xu, Guowang; Piao, Hai-long |
| 作者单位 | 1.Chinese Acad Sci, Dalian Inst Chem Phys, Sci Res Ctr Translat Med, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Dalian Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Dalian, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yan, Min,Qi, Huan,Xia, Tian,et al. Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPK alpha[J]. METABOLISM-CLINICAL AND EXPERIMENTAL,2019,91:18-29. |
| APA | Yan, Min.,Qi, Huan.,Xia, Tian.,Zhao, Xinjie.,Wang, Wen.,...&Piao, Hai-long.(2019).Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPK alpha.METABOLISM-CLINICAL AND EXPERIMENTAL,91,18-29. |
| MLA | Yan, Min,et al."Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPK alpha".METABOLISM-CLINICAL AND EXPERIMENTAL 91(2019):18-29. |
入库方式： OAI收割
来源：大连化学物理研究所
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