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Int. J. Mol. Sci. 2015, 16(11), 27228-27251; doi:10.3390/ijms161126018

Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells

1
Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
2
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
3
Department of Gynecologic Oncology Surgery, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang 550002, China
4
Department of Obstetrics and Gynecology, Xiaolan Hospital, Southern Medical University, Zhongshan 528415, China
5
Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang 550004, China
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 20 August 2015 / Revised: 2 November 2015 / Accepted: 5 November 2015 / Published: 13 November 2015
(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)
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Abstract

Ovarian carcinoma (OC) is one of the most common gynecological malignancies, with a poor prognosis for patients at advanced stage. Danusertib (Danu) is a pan-inhibitor of the Aurora kinases with unclear anticancer effect and underlying mechanisms in OC treatment. This study aimed to examine the cancer cell killing effect and explore the possible mechanisms with a focus on proliferation, cell cycle progression, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) in human OC cell lines C13 and A2780cp. The results showed that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both cell lines. Danu arrested cells in G2/M phase and led to an accumulation of polyploidy through the regulation of the expression key cell cycle modulators. Danu induced mitochondria-dependent apoptosis and autophagy in dose and time-dependent manners. Danu suppressed PI3K/Akt/mTOR signaling pathway, evident from the marked reduction in the phosphorylation of PI3K/Akt/mTOR, contributing to the autophagy inducing effect of Danu in both cell lines. In addition, Danu inhibited EMT. In aggregate, Danu exerts potent inducing effect on cell cycle arrest, apoptosis, and autophagy, but exhibits a marked inhibitory effect on EMT. PI3K/Akt/mTOR signaling pathway contributes, partially, to the cancer cell killing effect of Danu in C13 and A2780cp cells. View Full-Text
Keywords: danusertib; ovarian cancer; cell cycle; apoptosis; autophagy; epithelial to mesenchymal transition danusertib; ovarian cancer; cell cycle; apoptosis; autophagy; epithelial to mesenchymal transition
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Zi, D.; Zhou, Z.-W.; Yang, Y.-J.; Huang, L.; Zhou, Z.-L.; He, S.-M.; He, Z.-X.; Zhou, S.-F. Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells. Int. J. Mol. Sci. 2015, 16, 27228-27251.

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