Compound C enhances the anticancer effect of aspirin in HER-2-positive breast cancer by regulating lipid metabolism in an AMPK-independent pathway

Various clinical studies have determined that aspirin shows anticancer effects in many human malignant cancers, including human epidermal growth factor receptor-2 (HER-2)-positive breast cancer.However, the anti-tumor mechanism of aspirin has not been fully defined.The aim of this study was to determine the role of Compound C in enhancing the anticancer effect of aspirin.HER-2-positive breast cancer cell lines were treated with aspirin with or without Compound C pre-treatment; their phenotypes and mechanisms were then analyzed in vitro and in vivo.Aspirin exhibited anticancer effects in HER-2-positive breast cancer by inhibiting cell growth and inducing apoptosis through the activation of AMP-activated protein kinase (AMPK).Unexpectedly, pre-treatment with Compound C, a widely used AMPK inhibitor, induced robust anticancer effects in cells compared to aspirin monotherapy.This anticancer effect was not distinct in HER-2 negative breast cancer MDA-MB-231 cells and may be due to the inhibition of lipid metabolism mediated by c-myc.Besides, c-myc re-expression or palmitic acid supply could partially restored cell proliferation.Aspirin exhibits anticancer effects in HER-2-positive breast cancer by regulating lipid metabolism mediated by c-myc, and Compound C strengthens these effects in an AMPK-independent manner.Our results potentially provide a novel therapeutic strategy exploiting combined aspirin and Compound C therapy for HER-2-positive breast cancer, which acts by reducing de novo lipid synthesis.