The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers

The role of transcriptional factor FOXO1 in the mechanism of drug- resistance in ovarian cancer has not been elucidated. In ovarian cancer cell lines, FOXO1 expression and its correlation with paclitaxel treatment was investigated by cytotoxic assay and silencing experiment. Clinical ovarian cancer samples were also examined for FOXO1 expression by immunohistochemistry. FOXO1 expression was distinctively upregulated in paclitaxel- resistant cell line, and enhanced by exposure to paclitaxel. FOXO1 overexpression was frequently observed in tissue samples from chemoresistant patients compared to chemosensitive patients. FOXO1 silencing in paclitaxel- resistant cell line decreased its resistance. Modification of oxidative stress by co- treatment with pharmacologic modulators of reactive oxygen species attenuated cytotoxicity of paclitaxel. Downstream targets of FOXO1 involving oxidative stress were also attenuated in silencing experiment, suggesting its involvement in altered sensitivity to paclitaxel. These results indicate that FOXO1 links to cytotoxic stress induced by paclitaxel and contributes to the drug- resistance in ovarian cancers.