Eltrombopag Inhibits Metastasis in Breast Carcinoma by Targeting HuR Protein

• Published in: International journal of molecular sciences Vol. 24; no. 4; p. 3164
• Main Authors: Chen, Yao, Zhang, Rui, Yang, Liuqing, Zhang, Pei, Wang, Feiyun, Lin, Guoqiang, Zhang, Jiange, Zhu, Yuying
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2023; MDPI
• Subjects: Angiogenesis; Animal models; Animals; Antigens; Breast cancer; Breast carcinoma; Breast Neoplasms - metabolism; Cancer; Care and treatment; Cell adhesion & migration; Cell Line, Tumor; Colorectal cancer; Cyclooxygenase 2 - metabolism; Development and progression; ELAV-Like Protein 1; Eltrombopag; eltrombopag (ELB); Experiments; Female; Genes; Genetic aspects; Health aspects; Humans; HuR; HuR protein; Lung cancer; lung metastasis; lymph node metastasis; Lymph nodes; macrophage; Macrophages; Metastases; Metastasis; mRNA stability; Photographic industry; Proteins; RNA; Stability; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor C - genetics; Japan; China; breast cancer; macrophage; lung metastasis; HuR; eltrombopag (ELB); lymph node metastasis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24043164

Eltrombopag is a small molecule TPO-R agonist that has been shown in our previous studies to inhibit tumor growth by targeting Human antigen R (HuR) protein. HuR protein not only regulates the mRNA stability of tumor growth-related genes, but it also regulates the mRNA stability of a variety of cancer metastasis-related genes, such as , , and . However, the role and mechanisms of eltrombopag in breast cancer metastasis have not been fully investigated. The purpose of this study was to investigate whether eltrombopag can inhibit breast cancer metastasis by targeting HuR. Our study first found that eltrombopag can destroy HuR-AU-rich element (ARE) complexes at the molecular level. Secondly, eltrombopag was found to suppress 4T1 cell migration and invasion and inhibit macrophage-mediated lymphangiogenesis at the cellular level. In addition, eltrombopag exerted inhibitory effects on lung and lymph node metastasis in animal tumor metastasis models. Finally, it was verified that eltrombopag inhibited the expressions of , , and in 4T1 cells and in RAW264.7 cells by targeting HuR. In conclusion, eltrombopag displayed antimetastatic activity in breast cancer in an HuR dependent manner, which may provide a novel application for eltrombopag, hinting at the multiple effects of HuR inhibitors in cancer therapy.