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.
Highlights
Accumulating evidence indicates that the metabolic state of cancer stem cells (CSCs), a population of cancer cells capable of enhanced self-renewal, governs their tumor-initiating ability
We first tested the ability of MCF-7 breast cancer cells to form tumor spheres when grown in suspension cultures in the presence of a range of concentrations of soraphen A (1, 5, 10, and 50 nmol/L)
The ability of some CSC-like cellular states to survive and proliferate as floating spherical colonies under anchorage-independent conditions at low frequencies (1-3%) is commonly regarded as an in vitro surrogate of the self-renewal and tumor-initiating capacity exclusively possessed by CSCs, it should be acknowledged that mammosphere formation assays can be viewed as bona fide assays for evaluating the number of anoikis-resistant cells within heterogenous cancer populations
Summary
Accumulating evidence indicates that the metabolic state of cancer stem cells (CSCs), a population of cancer cells capable of enhanced self-renewal, governs their tumor-initiating ability. Efforts to inhibit glycolysis using the glucose analog 2-deoxyglucose (2DG), which accumulates in cells and inhibits glycolytic hexokinase (KH), or the small molecule dichloroacetate (DCA), which inhibits mitochondrial pyruvate dehydrogenase kinase (PDK) and forces pyruvate into the mitochondria to increase mitochondrial metabolism, remain unsatisfactory. These approaches www.impactjournals.com/oncotarget are not selective for either CSCs or more differentiated bulk tumor cells, and drugs that inhibit glycolysis do not necessarily result in increased mitochondrial metabolism and could result in the disruption of energy production and non-selective cell death. The mitochondrial regulator metformin has been increasingly recognized as a strong therapeutic capable of targeting CSCs in pre-clinical models of human cancer [13,14,15,16,17,18,19,20,21,22,23]
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