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Theranostics 2020; 10(15):6839-6853. doi:10.7150/thno.43622 This issue Cite

Research Paper

Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription

Gengyi Zou^1,2,4#, Xiaotong Zhang^1,4#, Lun Wang^3#, Xiyang Li^1,4, Tianyu Xie¹, Jin Zhao^1,4, Jie Yan¹, Longlong Wang^1,4, Haoyu Ye³, Shunchang Jiao², Rong Xiang^1,4✉, Yi Shi^1,4✉

1. School of Medicine, Nankai University, Tianjin 300071, China.
2. Department of Oncology, Chinese PLA General Hospital, Beijing 100853, China.
3. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
4. 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Tianjin 300071, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Yi Shi. E-mail: yishiedu.cn; Rong Xiang. E-mail: rxiangedu.cn.; School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; Phone: (86)-22-23509482, Fax: (86)-22-23502554.

Abstract

Anti-angiogenesis is an important and promising strategy in cancer therapy. However, the current methods using anti-vascular endothelial growth factor A (VEGFA) antibodies or inhibitors targeting VEGFA receptors are not as efficient as expected partly due to their low efficiencies in blocking VEGFA signaling in vivo. Until now, there is still no method to effectively block VEGFA production in cancer cells from the very beginning, i.e., from the transcriptional level. Here, we aimed to find bioactive small molecules to block VEGFA transcription.

Methods: We screened our natural compound pool containing 330 small molecules derived from Chinese traditional herbs for small molecules activating the expression of seryl-tRNA synthetase (SerRS), which is a newly identified potent transcriptional repressor of VEGFA, by a cell-based screening system in MDA-MB-231 cell line. The activities of the candidate molecules on regulating SerRS and VEGFA expression were first tested in breast cancer cells. We next investigated the antiangiogenic activity in vivo by testing the effects of candidate drugs on the vascular development in zebrafish and by matrigel plug angiogenesis assay in mice. We further examined the antitumor activities of candidate drugs in two triple-negative breast cancer (TNBC)-bearing mouse models. Furthermore, streptavidin-biotin affinity pull-down assay, coimmunoprecipitation assays, docking analysis and chromatin immunoprecipitation were performed to identify the direct targets of candidate drugs.

Results: We identified emodin that could greatly increase SerRS expression in TNBC cells, consequently reducing VEGFA transcription. Emodin potently inhibited vascular development of zebrafish and blocked tumor angiogenesis in TNBC-bearing mice, greatly improving the survival. We also identified nuclear receptor corepressor 2 (NCOR2) to be the direct target of emodin. Once bound by emodin, NCOR2 got released from SerRS promoter, resulting in the activation of SerRS expression and eventually the suppression of VEGFA transcription.

Conclusion: We discovered a herb-sourced small molecule emodin with the potential for the therapy of TNBC by targeting transcriptional regulators NCOR2 and SerRS to suppress VEGFA transcription and tumor angiogenesis.

Keywords: Emodin/NCOR2/SerRS/tumor angiogenesis/VEGFA

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