Corominas-Faja Bruna, Cuyàs Elisabet, Gumuzio Juan, Bosch-Barrera Joaquim, Leis Olatz, Martin Ángel G, Menendez Javier A
Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia Spain. Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia Spain.
Fundación Inbiomed, San Sebastián, Gipuzkoa Spain.
Oncotarget. 2014 Sep 30;5(18):8306-16. doi: 10.18632/oncotarget.2059.
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.
癌症干细胞（CSC）可能利用瓦伯格效应诱导的代谢中间体虹吸作用进入从头脂肪酸生物合成过程，以增加自我更新生长。我们研究了抗真菌聚酮化合物索拉非尼A的抗CSC作用，它是由乙酰辅酶A羧化酶（ACACA）催化的脂质生物合成第一步的特异性抑制剂。用索拉非尼A处理后，MCF-7细胞的乳腺球形成能力呈剂量依赖性降低。经过基因工程改造过表达癌基因HER2的MCF-7细胞（MCF-7/HER2细胞）对索拉非尼A诱导的乳腺球形成效率降低的敏感性比MCF-7亲代细胞高5倍。索拉非尼A处理显著减少了醛脱氢酶（ALDH）阳性的CSC样细胞，并阻碍了HER2增加ALDH+干细胞群体的能力。以下结果证实，索拉非尼A诱导的CSC群体抑制是通过ACACA驱动的脂肪生成发生的：a）在存在索拉非尼A的情况下，外源性补充超生理浓度的油酸可完全挽救乳腺球形成；b）稳定沉默特异性参与从头脂肪生成的胞质异构体ACACA1表达的MCF-7细胞的乳腺球培养物对索拉非尼A处理大多具有抗性。我们的研究结果首次揭示，ACACA可能构成一种以前未被认识的新型抗乳腺癌CSC疗法的靶点。
