miRNA-150 downregulation promotes pertuzumab resistance in ovarian cancer cells via AKT activation.

ABSTRACT

BACKGROUND: Pertuzumab is a humanized mAb that binds to the extracellular region of HER2/ErbB2 and is approved for treating breast cancer. Although ovarian cancer and breast cancer have comparable levels of HER2/ErbB2 expression, clinical studies of pertuzumab in epithelial ovarian cancer patients have not met the same level of success. OBJECTIVES: To investigate the molecular mechanisms by which pertuzumab exerts its anti-tumor effects in ovarian cancer and the mechanisms by which cancer cells achieve pertuzumab resistance. METHODS: We examined expression of miR-150 in ovarian cancer cells treated with pertuzumab or not. miR-150 knockdown impacts on pertuzumab treatment were analyzed by cell proliferation assay, apoptosis analysis and cell cycle analysis. Cell signal pathway was examined by western blot assay. RESULTS: Pertuzumab induced miRNA-150 expression in SKOV3 and SNU119 cells. Furthermore, suppression of miRNA-150 in both cell lines resulted in decreased drug sensitivity to pertuzumab and cell apoptosis. The blockage of G1/S checkpoint by pertuzumab was rescued as well. miRNA-150 knockdown activated PI3K-Akt pathway and LY294002 reversed the effect of miR-150 knockdown. CONCLUSIONS: miRNA-150 downregulation may contribute to the pertuzumab resistance in ovarian cancer via, at least in part, PI3K-akt pathway.