Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells
Metrics: PDF 2114 views | HTML 2040 views | ?
Bruna Corominas-Faja1,2, Elisabet Cuyàs1,2, Juan Gumuzio3, Joaquim Bosch-Barrera4, Olatz Leis5, Ángel G. Martin5 and Javier A. Menendez1,2
1 Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia Spain
2 Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia Spain
3 Fundación Inbiomed, San Sebastián, Gipuzkoa Spain
4 Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia Spain
5 StemTek Therapeutics; Bilbao, Biscay Spain
Javier A. Menendez, email:
Keywords: Acetyl-CoA Carboxylase; Cancer Stem Cells; Lipogenesis; Warburg effect; metabolism; breast cancer; Soraphen A
Received: April 7, 2014 Accepted: June 4, 2014 Published: June 5, 2014
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.