title: Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells.
abstract: Cancer stem cells (CSC) may take advantage of the Warburg effect-induced siphoning of metabolic intermediates into de novo fatty acid biosynthesis to increase self-renewal growth. We examined the anti-CSC effects of the antifungal polyketide soraphen A, a specific inhibitor of the first committed step of lipid biosynthesis catalyzed by acetyl-CoA carboxylase (ACACA). The mammosphere formation capability of MCF-7 cells was reduced following treatment with soraphen A in a dose-dependent manner. MCF-7 cells engineered to overexpress the oncogene HER2 (MCF-7/HER2 cells) were 5-fold more sensitive than MCF-7 parental cells to soraphen A-induced reductions in mammosphere-forming efficiency. Soraphen A treatment notably decreased aldehyde dehydrogenase (ALDH)-positive CSC-like cells and impeded the HER2's ability to increase the ALDH+-stem cell population. The following results confirmed that soraphen A-induced suppression of CSC populations occurred throughACACA-driven lipogenesis: a.) exogenous supplementation with supraphysiological concentrations of oleic acid fully rescued mammosphere formation in the presence of soraphen A and b.) mammosphere cultures of MCF-7 cells with stably silenced expression of the cytosolic isoform ACACA1, which specifically participates in de novo lipogenesis, were mostly refractory to soraphen A treatment. Our findings reveal for the first time that ACACA may constitute a previously unrecognized target for novel anti-breast CSC therapies.
authors.affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia Spain. Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia Spain.
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia Spain. Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: Fundación Inbiomed, San Sebastián, Gipuzkoa Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Gumuzio
authors.affiliation: Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.affiliation: StemTek Therapeutics, Bilbao, Biscay Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Leis
authors.affiliation: StemTek Therapeutics, Bilbao, Biscay Spain.
authors.forename: Ángel G
authors.initials: ÁG
authors.lastname: Martin
authors.affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia Spain. Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D061986:MCF-7 Cells; D018942:Macrolides / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019301:Oleic Acid / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D014162:Transfection
chemical_list: D000103:Acetyl-CoA Carboxylase; D000444:Aldehyde Dehydrogenase; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D019301:Oleic Acid; D018719:Erb-b2 Receptor Tyrosine Kinases; C086151:soraphen A; C508053:ERBB2 protein, human; C000588423:ACACA protein, human