title: Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth.
abstract: Tumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate metabolism remains to be clarified. We show that glutamine supplementation is not sufficient to prevent loss of cell viability in a subset of glucose-deprived melanoma cells, but synergizes with acetate to support cell survival. Glucose-deprived melanoma cells depend on both oxidative phosphorylation and acetate metabolism for cell survival. Acetate supplementation significantly contributed to maintenance of ATP levels in glucose-starved cells. Unlike acetate, short chain fatty acids such as butyrate and propionate failed to prevent loss of cell viability from glucose deprivation. In vivo studies revealed that in addition to nucleo-cytoplasmic acetate assimilating enzyme ACSS2, mitochondrial ACSS1 was critical for melanoma tumor growth in mice. Our data indicate that acetate metabolism may be a potential therapeutic target for BRAF mutant melanoma.
authors.affiliation: From the Department of Immunology and Microbiology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lakhter
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: James
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Konger
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
authors.affiliation: From the Department of Immunology and Microbiology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
authors.affiliation: From the Department of Immunology and Microbiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, naidus@iu.edu.
authors.forename: Samisubbu R
authors.identifier: http://orcid.org/0000-0001-9411-660X
authors.initials: SR
authors.lastname: Naidu
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020148:Butyric Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D010085:Oxidative Phosphorylation; D011422:Propionates / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism
chemical_list: D000085:Acetates; D011422:Propionates; D020148:Butyric Acid; D000255:Adenosine Triphosphate; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; C029658:propionic acid
keywords: ACSS1; ACSS2; acetate metabolism; acetyl-CoA synthetase; bioenergetics; glucose metabolism; glutamine; glycolysis; melanoma; mitochondria