Int J Biol Sci 2020; 16(4):583-597. doi:10.7150/ijbs.39936

Research Paper

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

Ying Wu1,2*, Bohua Yan3*, Wenqin Xu4, Lili Guo1, Zhe Wang1, Guoyin Li5, Niuniu Hou1, Jian Zhang2✉, Rui Ling1✉

1. Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
2. Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
3. Fourth Military Medical University, Xi'an, Shaanxi, China.
4. Department of Ophthalmology, Eye Institute of China PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
5. College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, Henan, China.
*Ying Wu and Bohua Yan should be considered joint first author.

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Citation:
Wu Y, Yan B, Xu W, Guo L, Wang Z, Li G, Hou N, Zhang J, Ling R. Compound C enhances the anticancer effect of aspirin in HER-2-positive breast cancer by regulating lipid metabolism in an AMPK-independent pathway. Int J Biol Sci 2020; 16(4):583-597. doi:10.7150/ijbs.39936. Available from http://www.ijbs.com/v16p0583.htm

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Abstract

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.

Keywords: HER-2-positive breast cancer, aspirin, Compound C, lipid metabolism, c-myc.