Abstract
BackgroundOvarian cancer is the most common malignant tumor of the female reproductive tract. Chemoresistance is a major challenge for current ovarian cancer therapy. However, the mechanism underlying epithelial ovarian cancer (EOC) chemoresistance is not completely uncovered. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important intracellular pathway in regulating cell cycle, quiescence, and proliferation. The aim of this study is to investigate the role of PI3K/Akt/mTOR signaling pathway and its association with epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) marker expression in EOC chemoresistance.MethodsThe expressions of EMT and CSC markers were detected by immunofluorescence, western blot, and quantitative real-time PCR. BEZ235, a dual PI3K/mTOR inhibitor, was employed to investigate the role of PI3K/Akt/ mTOR signaling in regulating EMT and CSC marker expression. Students’ t test and one-way ANOVA with Tukey’s post-hoc test were used to compare the data from different groups.ResultsWe found that EMT and CSC marker expression were significantly enhanced in chemoresistant EOC cells, which was accompanied by the activation of PI3K/Akt/mTOR signaling. Compared with single cisplatin treatment, combined treatment with BEZ235 and cisplatin significantly disrupted the colony formation ability, induced higher ROS level and more apoptosis in chemoresistant EOC cells. Furthermore, the combination approach effectively inhibited PI3K/Akt/mTOR signaling pathway, reversed EMT, and decreased CSC marker expression in chemoresistant EOC cells compared with cisplatin mono-treatment.ConclusionsOur results first demonstrate that EMT and enhanced CSC marker expression triggered by activated PI3K/Akt/mTOR signaling are involved in the chemoresistance of EOC, and BEZ235 in combination with cisplatin might be a promising treatment option to reverse EOC chemoresistance.
Highlights
Ovarian cancer is the most common malignant tumor of the female reproductive tract
We found that the acquisition of epithelialmesenchymal transition (EMT) and enhancement of cancer stem cell (CSC) marker expression in chemoresistant epithelial ovarian cancer (EOC) cells were associated with the activation of PI3K/Protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling
The results showed that both p-Akt and p-mTOR were up-regulated in EOC-cis cells, while the increased expression of t-mTOR was only observed in A2780-cis cells (Fig. 3a), suggesting that PI3K/Akt/ mTOR signaling was activated in EOC-cis cells
Summary
Ovarian cancer is the most common malignant tumor of the female reproductive tract. Chemoresistance is a major challenge for current ovarian cancer therapy. The mechanism underlying epithelial ovarian cancer (EOC) chemoresistance is not completely uncovered. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important intracellular pathway in regulating cell cycle, quiescence, and proliferation. The aim of this study is to investigate the role of PI3K/Akt/mTOR signaling pathway and its association with epithelialmesenchymal transition (EMT) and cancer stem cell (CSC) marker expression in EOC chemoresistance. Ovarian cancer is the most common malignant tumor of the female reproductive tract. Thereinto, EOC is the most common type and accounts for approximately 90% of ovarian malignancy [2]. Studies from different groups indicated that epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) were closely associated with the chemoresistance, metastasis and tumor relapse in EOC patients [3]. The role of EMT in EOC chemoresistance is not fully elucidated
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