Abstract | BACKGROUND: 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 Ampkα-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 Ampkα-dependently upregulated P-Acc but Ampkα-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-Aminoimidazole-4-carboxamide ribonucleotide ( AICAR) and fetal bovine serum (FBS) starvation, as a common model for energy stress, both led to Ampkα-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 Ampkα-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 Ampkα, and may provide a new insight for its clinical usage.
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Authors | Min Yan, Huan Qi, Tian Xia, Xinjie Zhao, Wen Wang, Zhichao Wang, Chang Lu, Zhen Ning, Huan Chen, Tongming Li, Dinesh Singh Tekcham, Xiumei Liu, Jing Liu, Di Chen, Xiaolong Liu, Guowang Xu, Hai-Long Piao |
Journal | Metabolism: clinical and experimental
(Metabolism)
Vol. 91
Pg. 18-29
(02 2019)
ISSN: 1532-8600 [Electronic] United States |
PMID | 30468782
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 Elsevier Inc. All rights reserved. |
Chemical References |
- Enzyme Inhibitors
- Hypoglycemic Agents
- Ribonucleotides
- Lactic Acid
- Aminoimidazole Carboxamide
- Metformin
- AMPK alpha1 subunit, mouse
- AMP-Activated Protein Kinases
- AICA ribonucleotide
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Topics |
- AMP-Activated Protein Kinases
(antagonists & inhibitors, drug effects, genetics)
- Aminoimidazole Carboxamide
(analogs & derivatives, pharmacology)
- Animals
- Cell Line, Tumor
- Citric Acid Cycle
(drug effects)
- Energy Metabolism
(drug effects)
- Enzyme Inhibitors
(pharmacology)
- Fibroblasts
(drug effects, metabolism)
- Humans
- Hypoglycemic Agents
(pharmacology)
- Lactic Acid
(metabolism)
- Metabolic Networks and Pathways
(drug effects)
- Metabolomics
(methods)
- Metformin
(pharmacology)
- Mice
- Mice, Knockout
- Ribonucleotides
(pharmacology)
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