Eltrombopag inhibits metastasis via targeting HuR protein in breast carcinoma

Background: Metastatic of breast cancer is one of the leading causes of cancer-related death. HuR is an mRNA binding protein, which could regulate mRNA stability of multiple cancer-related genes, including metastasis-related genes Snail , Cox-2 and Vegf-c . Eltrombopag is a small molecule TPO-R agonist which has been demonstrated to inhibit tumor growth by targeting HuR protein. However, the effect and mechanisms of eltrombopag in breast cancer metastasis has not been fully investigated. This study aimed to investigated the role of eltrombopag in breast cancer metastasis. Methods Activity of eltrombopag on molecular level was detected with Electrophoretic mobility shift assay (EMSA) and Fluorescence polarization (FP). Scratch wound assay and transwell assays were carried out to verified cell migration and invasion. Moreover, mechanism of HuR-dependent inhibition of breast cancer metastasis was identified with qRT-PCR, mRNA stability assay, RNA immunoprecipitation analysis and luciferase assays. The effect of anti-tumor metastasis in vivo was investigated by in vivo imaging system. Results We found that HuR-AREs complexes were disrupted by eltrombopag at molecular levels. Functionally, eltrombopag suppressed 4T1 cell migration and invasion, inhibited macrophage-mediated lymphangiogenesis in vitro . Mechanistically, eltrombopag was verified to inhibit the expression of Snail , Cox-2 , Vegf-c in 4T1 cells and Vegf-c in RAW264.7 cells through targeting HuR. Finally, eltrombopag exerts inhibitory effects in lung metastasis and lymph node metastasis in vivo . Conclusions Eltrombopag display anti-metastasis activity in breast cancer with HuR dependent manner, which may provide a novel application of eltrombopag and imply the multiple effects of HuR inhibitors in cancer therapy.