PMID- 31234823 OWN - NLM STAT- MEDLINE DCOM- 20191211 LR - 20211204 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 19 IP - 1 DP - 2019 Jun 24 TI - Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. PG - 618 LID - 10.1186/s12885-019-5824-9 [doi] LID - 618 AB - 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. FAU - Deng, Junli AU - Deng J AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. AD - Department of Gynaecological Oncology, Henan Cancer Hospital, Henan, 450008, China. FAU - Bai, Xupeng AU - Bai X AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. FAU - Feng, Xiaojie AU - Feng X AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. AD - Department of Gynaecological Oncology, Henan Cancer Hospital, Henan, 450008, China. FAU - Ni, Jie AU - Ni J AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. FAU - Beretov, Julia AU - Beretov J AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. AD - Anatomical Pathology, NSW Health Pathology, St. George Hospital, Kogarah, NSW, 2217, Australia. FAU - Graham, Peter AU - Graham P AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. FAU - Li, Yong AU - Li Y AD - Cancer Care Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia. y.li@unsw.edu.au. AD - St George and Sutherland Clinical School, UNSW Sydney, Kensington, NSW, 2052, Australia. y.li@unsw.edu.au. AD - School of Basic Medical Sciences, Zhengzhou University, Henan, 450001, China. y.li@unsw.edu.au. LA - eng GR - N/A/China Sponsorship Council/ GR - N/A/China Sponsorship Council/ PT - Journal Article DEP - 20190624 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Imidazoles) RN - 0 (Quinolines) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - Q20Q21Q62J (Cisplatin) RN - RUJ6Z9Y0DT (dactolisib) SB - IM MH - Analysis of Variance MH - Apoptosis/drug effects MH - Carcinoma, Ovarian Epithelial/*metabolism/pathology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cisplatin/pharmacology MH - Drug Resistance, Neoplasm/*drug effects MH - Epithelial-Mesenchymal Transition/*drug effects MH - Female MH - Humans MH - Imidazoles/pharmacology MH - Neoplastic Stem Cells/*metabolism MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Quinolines/pharmacology MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC6591840 OTO - NOTNLM OT - CSC OT - Chemoresistance OT - EMT OT - Ovarian cancer OT - PI3K/Akt/mTOR signaling COIS- The authors declare that they have no competing interests. EDAT- 2019/06/27 06:00 MHDA- 2019/12/18 06:00 PMCR- 2019/06/24 CRDT- 2019/06/26 06:00 PHST- 2019/03/22 00:00 [received] PHST- 2019/06/12 00:00 [accepted] PHST- 2019/06/26 06:00 [entrez] PHST- 2019/06/27 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2019/06/24 00:00 [pmc-release] AID - 10.1186/s12885-019-5824-9 [pii] AID - 5824 [pii] AID - 10.1186/s12885-019-5824-9 [doi] PST - epublish SO - BMC Cancer. 2019 Jun 24;19(1):618. doi: 10.1186/s12885-019-5824-9.