Abstract
Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.
Highlights
INTRODUCTIONOvarian cancer is the second most common gynecological malignancy and a major contributor to death from cancer in women [1]
Chemoresistance is a major obstacle in ovarian cancer therapyOvarian cancer is the second most common gynecological malignancy and a major contributor to death from cancer in women [1]
We show that FOXM1 is a critical regulator of the epithelial-mesenchymal transition (EMT), stemness, and chemoresistance in ovarian cancer cells
Summary
Ovarian cancer is the second most common gynecological malignancy and a major contributor to death from cancer in women [1]. CSCs acquire changes that confer drug resistance and a selection advantage, eventually generating a new population of chemoresistant cancer cells [5, 6]. Zhang et al found that WNT3A increases the abundance of nuclear FOXM1, which interacts with and promotes the nuclear accumulation and transcriptional activity of β-CATENIN in tumor cells [27]. Both proteins formed a complex with the TCF transcription factors on the promoters of WNT/β-CATENIN target genes. A clinical investigation established a relationship between FOXM1 expression and unfavorable outcomes in EOC patients, validating our in vitro findings
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