Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression

Abstract

Background Ovarian 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. Methods The 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. Results We 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. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5824-9) contains supplementary material, which is available to authorized users.

Targeting cancer stem cell pathways for cancer therapy

“…358 PI3K/Akt/mTOR signaling is involved in ovarian cancer cell proliferation and the epithelial-mesenchymal transition. 367 This signaling activation also enhances the migration and invasion of prostate and pancreatic CSCs. 368,369 Downregulation of PTEN induces PI3K activation to promote survival, maintenance of stemness, and tumorigenicity of CD133 + /CD44 + prostate cancer stem-like cell populations.…”

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

“…These pathways have critical roles in regulating tumor initiation, tumor growth, cell senescence, cell death, differentiation, and metastasis in various stages of cancer. The increased mitogenic signaling pathways of PI3K/AKT and MEK/ERK result in continued chronic proliferation in cancer cells [44][45][46][47]. We previously reported the activation of PI3K/AKT, MEK/ERK in cancer cells [48].…”

In Vitro Investigation of The Cytotoxic Activity of E35 on Multiple Myeloma Cell Lines

“…The Akt/mTOR/4EBP1 pathway has recently been recognized as one of key signal transduction pathways that suppress cellular apoptosis through phosphorylation and that subsequently induce the deactivation of downstream molecules of mTOR [30,31]. 4EBP1 is a downstream protein of mTOR, which inhibits eIF4E (the subunit of eIF4F).…”