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Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells.
Drug Des Devel Ther. 2015; 9:425-64.DD

Abstract

Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5'-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer cells. Further studies are warranted to validate the efficacy and safety of ALS in the treatment of ovarian cancer.

Authors+Show Affiliations

Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's Republic of China.Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China.Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China.Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China.Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China.School of Medicine, Deakin University, Waurn Ponds, Australia.Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's Republic of China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25624750

Citation

Ding, Yong-Hui, et al. "Alisertib, an Aurora Kinase a Inhibitor, Induces Apoptosis and Autophagy but Inhibits Epithelial to Mesenchymal Transition in Human Epithelial Ovarian Cancer Cells." Drug Design, Development and Therapy, vol. 9, 2015, pp. 425-64.
Ding YH, Zhou ZW, Ha CF, et al. Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells. Drug Des Devel Ther. 2015;9:425-64.
Ding, Y. H., Zhou, Z. W., Ha, C. F., Zhang, X. Y., Pan, S. T., He, Z. X., Edelman, J. L., Wang, D., Yang, Y. X., Zhang, X., Duan, W., Yang, T., Qiu, J. X., & Zhou, S. F. (2015). Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells. Drug Design, Development and Therapy, 9, 425-64. https://doi.org/10.2147/DDDT.S74062
Ding YH, et al. Alisertib, an Aurora Kinase a Inhibitor, Induces Apoptosis and Autophagy but Inhibits Epithelial to Mesenchymal Transition in Human Epithelial Ovarian Cancer Cells. Drug Des Devel Ther. 2015;9:425-64. PubMed PMID: 25624750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells. AU - Ding,Yong-Hui, AU - Zhou,Zhi-Wei, AU - Ha,Chun-Fang, AU - Zhang,Xue-Yu, AU - Pan,Shu-Ting, AU - He,Zhi-Xu, AU - Edelman,Jeffrey L, AU - Wang,Dong, AU - Yang,Yin-Xue, AU - Zhang,Xueji, AU - Duan,Wei, AU - Yang,Tianxin, AU - Qiu,Jia-Xuan, AU - Zhou,Shu-Feng, Y1 - 2015/01/09/ PY - 2015/1/28/entrez PY - 2015/1/28/pubmed PY - 2015/9/10/medline KW - Aurora kinase A KW - alisertib KW - apoptosis KW - autophagy KW - cell cycle KW - epithelial ovarian cancer KW - epithelial to mesenchymal transition KW - sirtuin 1 SP - 425 EP - 64 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 9 N2 - Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5'-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer cells. Further studies are warranted to validate the efficacy and safety of ALS in the treatment of ovarian cancer. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/25624750/Alisertib_an_Aurora_kinase_A_inhibitor_induces_apoptosis_and_autophagy_but_inhibits_epithelial_to_mesenchymal_transition_in_human_epithelial_ovarian_cancer_cells_ L2 - https://dx.doi.org/10.2147/DDDT.S74062 DB - PRIME DP - Unbound Medicine ER -