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Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2016 Nov 25; Vol. 291 (48), pp. 25154-25166. Date of Electronic Publication: 2016 Oct 12. - Publication Year :
- 2016
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Abstract
- AMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetyl-CoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects.<br /> (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- AMP-Activated Protein Kinases genetics
Acetyl Coenzyme A genetics
Acetyl Coenzyme A metabolism
Acetylation drug effects
Female
Gene Expression Regulation, Neoplastic genetics
HeLa Cells
Humans
Male
Malonyl Coenzyme A genetics
Malonyl Coenzyme A metabolism
Neoplasm Proteins genetics
Ovarian Neoplasms genetics
Prostatic Neoplasms genetics
Protein Processing, Post-Translational genetics
AMP-Activated Protein Kinases metabolism
Gene Expression Regulation, Neoplastic drug effects
Metformin pharmacology
Neoplasm Proteins metabolism
Ovarian Neoplasms metabolism
Prostatic Neoplasms metabolism
Protein Processing, Post-Translational drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 291
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27733682
- Full Text :
- https://doi.org/10.1074/jbc.M116.742247