title: Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells.
abstract: Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Jessica E C
authors.initials: JE
authors.lastname: Jones
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: William P
authors.initials: WP
authors.lastname: Esler
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Rushi
authors.initials: R
authors.lastname: Patel
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Adhiraj
authors.initials: A
authors.lastname: Lanba
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Vera
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Cecile
authors.initials: C
authors.lastname: Vernochet
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; C000588423:ACACA protein, human; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase