title: Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells.
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.
authors.affiliation: From the Department of Biological Sciences, St. John's University, Queens, New York 11439.
authors.forename: Luciano
authors.initials: L
authors.lastname: Galdieri
authors.affiliation: From the Department of Biological Sciences, St. John's University, Queens, New York 11439.
authors.forename: Himavanth
authors.initials: H
authors.lastname: Gatla
authors.affiliation: From the Department of Biological Sciences, St. John's University, Queens, New York 11439.
authors.forename: Ivana
authors.initials: I
authors.lastname: Vancurova
authors.affiliation: From the Department of Biological Sciences, St. John's University, Queens, New York 11439 vancuraa@stjohns.edu.
authors.forename: Ales
authors.initials: A
authors.lastname: Vancura
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008316:Malonyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated kinase (AMPK); acetyl coenzyme A (acetyl-CoA); cancer; histone acetylation; metformin; transcription