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 through ACACA-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.

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

“…Soraphen A is a natural product polyketide that potently inhibits ACAC (Vahlensieck et al, 1994;Bourbeau and Bartberger, 2015). This compound has been used to demonstrate that ACACA inhibition in cancer stem cells inhibited FA synthesis and resulted in cell death (Corominas-Faja et al, 2014). In HepG2 and LnCaP cells, both malonyl-CoA and FA levels decreased following ACACA inhibition by Soraphen A (Jump et al, 2011).…”

Lipid Synthesis Is a Metabolic Liability of Non–Small Cell Lung Cancer

“…Several lines of evidence support the rational for targeted ACC inhibition in oncology. Short interfering RNA (siRNA) knockdown of ACC1 expression induced apo- ptosis in prostate (Brusselmans et al 2005) and breast (Chajes et al 2006) cancer cells and in cisplatin-resistant lung cancer cell lines (Wangpaichitr et al 2012), and chemical inhibition of ACC1 and ACC2 by the macrocyclic myxobacterial natural product Soraphen A led to growth arrest in breast cancer cells (Beckers et al 2007) and induction of apoptosis in prostate cancer cells (Corominas-Faja et al 2014). Constitutively active ACC mutants also protected head and neck squamous cancer cells from cetuximab-induced growth inhibition (Luo et al 2016).…”

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…91,92 Beyond the fact that fatty acids can play a shared role in normal and cancerous stem cell energy generation via fatty acid oxidation, pharmacological inhibition of ACACA and FASN efficiently impedes the formation of mammospheres in a fatty acid-dependent manner, strongly suggesting that the self-renewal and survival of CSC can be directly impacted by de novo lipogenesis, lipid metabolites, and lipid catabolism. 93,94 With regard to the latter, overexpression of monoacylglycerol lipase (MAGL) in nonaggressive cancer cells is sufficient to increase their pathogenicity by recapitulating a fatty acid network enriched in oncogenic signaling lipids that promote migration, invasion, survival, and in vivo tumor growth. 95,96 Given the unique role of MAGL in providing lipolytic sources of free fatty acids for the synthesis of oncogenic signaling lipids, CSCs might co-opt lipolytic enzymes such as MAGL to translate their lipogenic state of stem cells into an array of protumorigenic signals.…”