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Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway.
Drug Des Devel Ther. 2015; 9:1555-84.DD

Abstract

Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy.

Authors+Show Affiliations

Department of Spinal Surgery, 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 Orthopedics, General Hospital of Tianjin Medical University, Tianjin, People's Republic of China.Department of Spinal Surgery, 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 Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.Department of Spinal Surgery, 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.Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 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, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.Department of Biochemistry, Medical Center, Rush University, Chicago, IL, USA.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.Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.Department of General Surgery, The First People's Hospital of Shunde affiliated to Southern Medical University, Foshan, Guangdong, People's Republic of China.Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25792811

Citation

Niu, Ning-Kui, et al. "Pro-apoptotic and Pro-autophagic Effects of the Aurora Kinase a Inhibitor Alisertib (MLN8237) On Human Osteosarcoma U-2 OS and MG-63 Cells Through the Activation of Mitochondria-mediated Pathway and Inhibition of P38 MAPK/PI3K/Akt/mTOR Signaling Pathway." Drug Design, Development and Therapy, vol. 9, 2015, pp. 1555-84.
Niu NK, Wang ZL, Pan ST, et al. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther. 2015;9:1555-84.
Niu, N. K., Wang, Z. L., Pan, S. T., Ding, H. Q., Au, G. H., He, Z. X., Zhou, Z. W., Xiao, G., Yang, Y. X., Zhang, X., Yang, T., Chen, X. W., Qiu, J. X., & Zhou, S. F. (2015). Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Design, Development and Therapy, 9, 1555-84. https://doi.org/10.2147/DDDT.S74197
Niu NK, et al. Pro-apoptotic and Pro-autophagic Effects of the Aurora Kinase a Inhibitor Alisertib (MLN8237) On Human Osteosarcoma U-2 OS and MG-63 Cells Through the Activation of Mitochondria-mediated Pathway and Inhibition of P38 MAPK/PI3K/Akt/mTOR Signaling Pathway. Drug Des Devel Ther. 2015;9:1555-84. PubMed PMID: 25792811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. AU - Niu,Ning-Kui, AU - Wang,Zi-Li, AU - Pan,Shu-Ting, AU - Ding,Hui-Qiang, AU - Au,Giang H T, AU - He,Zhi-Xu, AU - Zhou,Zhi-Wei, AU - Xiao,Guozhi, AU - Yang,Yin-Xue, AU - Zhang,Xueji, AU - Yang,Tianxin, AU - Chen,Xiao-Wu, AU - Qiu,Jia-Xuan, AU - Zhou,Shu-Feng, Y1 - 2015/03/12/ PY - 2015/3/21/entrez PY - 2015/3/21/pubmed PY - 2016/8/10/medline KW - ALS KW - EMT KW - PI3K/Akt/mTOR pathway KW - apoptosis KW - autophagy KW - osteosarcoma SP - 1555 EP - 84 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 9 N2 - Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/25792811/Pro_apoptotic_and_pro_autophagic_effects_of_the_Aurora_kinase_A_inhibitor_alisertib__MLN8237__on_human_osteosarcoma_U_2_OS_and_MG_63_cells_through_the_activation_of_mitochondria_mediated_pathway_and_inhibition_of_p38_MAPK/PI3K/Akt/mTOR_signaling_pathway_ L2 - https://dx.doi.org/10.2147/DDDT.S74197 DB - PRIME DP - Unbound Medicine ER -