Anlotinib Suppresses Growth and Metastasis Through MAPK Signaling Pathway in Cisplatin-Resistant Ovarian Cancer Cells.

e17542 Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Increasing evidence suggests that anlotinib exhibits effective anti-tumor activity in various cancer types. However, the functional roles of anlotinib on cisplatin-resistant ovarian cancer are yet to be elucidated. The objective of this study was to investigate the anti-tumor effects of anlotinib in the pathogenesis of cisplatin-resistant ovarian cancer cells and tried to explore the related molecular mechanisms. Methods: Human ovarian cancer cells (A2780 and A2780 CIS) were cultured and treated with or without anlotinib. The effects of anlotinib on cells proliferation were determined by CCK-8 assay and colony formation assay. To evaluate the invasion and metastasis of ovarian cancer cells, we conducted wound healing and trans-well assay. Cell cycle was detected by flow cytometry. Moreover, the xenograft mouse model was used for conducting in vivo studies to verify the effect of anlotinib. The expression of Ki-67 in the tumor tissue was detected by immunohistochemistry. In GSE15372, differential expressed genes (DEGs) between cisplatin-sensitive and cisplatin-resistant groups were analyzed and enriched pathways were identified. Real-time qPCR and Western blot were used to measure the mRNA or protein level. Results: In vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration, and invasion restraint. Meanwhile, xenograft cisplatin-resistant ovarian tumor models revealed that anlotinib treatment dramatically hindered in vivo tumor cells growth. HE and Ki-67 staining showed anlotinib markedly inhibited cisplatin-resistant ovarian cancer cells proliferation. Polo-like kinase 2 (Plk2) was identified as the main target gene of cisplatin-resistant ovarian cancer cells through bioinformatics analysis. Furthermore, we found that anlotinib upregulated the expression of Plk2 and suppressed the MAPK signaling pathway activation. The high expression of Plk2 might serve as a promising indicator when used to predict a favorable therapeutic response. Conclusions: In this study, we found that anlotinib had excellent anti-tumor effects in cisplatin-resistant ovarian cancer cells both in vitro and in vivo. These present results add to the growing body of evidence supporting anlotinib as a potential anti-cancer agent in ovarian cancer.