PMID- 25834401 OWN - NLM STAT- MEDLINE DCOM- 20160517 LR - 20211203 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 9 DP - 2015 TI - The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells. PG - 1627-52 LID - 10.2147/DDDT.S75378 [doi] AB - Alisertib (ALS) is an investigational potent Aurora A kinase inhibitor currently undergoing clinical trials for the treatment of hematological and non-hematological malignancies. However, its antitumor activity has not been tested in human breast cancer. This study aimed to investigate the effect of ALS on the growth, apoptosis, and autophagy, and the underlying mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. In the current study, we identified that ALS had potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects in MCF7 and MDA-MB-231 cells. ALS arrested the cells in G2/M phase in MCF7 and MDA-MB-231 cells which was accompanied by the downregulation of cyclin-dependent kinase (CDK)1/cell division cycle (CDC) 2, CDK2, and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53, suggesting that ALS induces G2/M arrest through modulation of p53/p21/CDC2/cyclin B1 pathways. ALS induced mitochondria-mediated apoptosis in MCF7 and MDA-MB-231 cells; ALS significantly decreased the expression of B-cell lymphoma 2 (Bcl-2), but increased the expression of B-cell lymphoma 2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and increased the expression of cleaved caspases 3 and 9. ALS significantly increased the expression level of membrane-bound microtubule-associated protein 1 light chain 3 (LC3)-II and beclin 1 and induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways in MCF7 and MDA-MB-231 cells as indicated by their altered phosphorylation, contributing to the pro-autophagic activities of ALS. Furthermore, treatment with wortmannin markedly downregulated ALS-induced p38 MAPK activation and LC3 conversion. In addition, knockdown of the p38 MAPK gene by ribonucleic acid interference upregulated Akt activation and resulted in LC3-II accumulation. These findings indicate that ALS promotes cellular apoptosis and autophagy in breast cancer cells via modulation of p38 MAPK/Akt/mTOR pathways. Further studies are warranted to further explore the molecular targets of ALS in the treatment of breast cancer. FAU - Li, Jin-Ping AU - Li JP AD - Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA. FAU - Yang, Yin-Xue AU - Yang YX AD - Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China. FAU - Liu, Qi-Lun AU - Liu QL AD - Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China. FAU - Pan, Shu-Ting AU - Pan ST AD - Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 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. FAU - He, Zhi-Xu AU - He ZX AD - 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. FAU - Zhang, Xueji AU - Zhang X AD - Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China. FAU - Yang, Tianxin AU - Yang T AD - Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA. FAU - Chen, Xiao-Wu AU - Chen XW AD - Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, People's Republic of China. FAU - Wang, Dong AU - Wang D AD - Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China. FAU - Qiu, Jia-Xuan AU - Qiu JX AD - Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China. FAU - Zhou, Shu-Feng AU - Zhou SF AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150316 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (Azepines) RN - 0 (MLN 8237) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - EC 2.7.11.1 (AURKA protein, human) RN - EC 2.7.11.1 (Aurora Kinase A) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Apoptosis/*drug effects MH - Aurora Kinase A/antagonists & inhibitors/metabolism MH - Autophagy/*drug effects MH - Azepines/chemical synthesis/chemistry/*pharmacology MH - Breast Neoplasms/*drug therapy/metabolism/pathology MH - Cell Cycle/*drug effects MH - Cell Division/drug effects MH - Cell Proliferation/drug effects MH - Dose-Response Relationship, Drug MH - Drug Screening Assays, Antitumor MH - Female MH - G2 Phase Cell Cycle Checkpoints/drug effects MH - Humans MH - M Phase Cell Cycle Checkpoints/drug effects MH - MAP Kinase Signaling System/*drug effects MH - MCF-7 Cells MH - Protein Kinase Inhibitors/chemical synthesis/chemistry/pharmacology MH - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism MH - Pyrimidines/chemical synthesis/chemistry/*pharmacology MH - Structure-Activity Relationship MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Tumor Cells, Cultured MH - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism PMC - PMC4365748 OTO - NOTNLM OT - ALS OT - apoptosis OT - autophagy OT - breast cancer OT - cell cycle OT - p38 MAPK EDAT- 2015/04/04 06:00 MHDA- 2016/05/18 06:00 PMCR- 2015/03/16 CRDT- 2015/04/03 06:00 PHST- 2015/04/03 06:00 [entrez] PHST- 2015/04/04 06:00 [pubmed] PHST- 2016/05/18 06:00 [medline] PHST- 2015/03/16 00:00 [pmc-release] AID - dddt-9-1627 [pii] AID - 10.2147/DDDT.S75378 [doi] PST - epublish SO - Drug Des Devel Ther. 2015 Mar 16;9:1627-52. doi: 10.2147/DDDT.S75378. eCollection 2015.