PMID- 25609923 OWN - NLM STAT- MEDLINE DCOM- 20150909 LR - 20220321 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 9 DP - 2015 TI - Inhibition of mitotic Aurora kinase A by alisertib induces apoptosis and autophagy of human gastric cancer AGS and NCI-N78 cells. PG - 487-508 LID - 10.2147/DDDT.S74127 [doi] AB - Gastric cancer is one of the most common cancers and responds poorly to current chemotherapy. Alisertib (ALS) is a second-generation, orally bioavailable, highly selective small-molecule inhibitor of the serine/threonine protein kinase Aurora kinase A (AURKA). ALS has been shown to have potent anticancer effects in preclinical and clinical studies, but its role in gastric cancer treatment is unclear. This study aimed to investigate the cancer cell-killing effect of ALS on gastric cancer cell lines AGS and NCI-N78, with a focus on cell proliferation, cell-cycle distribution, apoptosis, and autophagy and the mechanism of action. The results showed that ALS exhibited potent growth-inhibitory, proapoptotic, and proautophagic effects on AGS and NCI-N78 cells. ALS concentration-dependently inhibited cell proliferation and induced cell-cycle arrest at G2/M phase in both cell lines, with a downregulation of cyclin-dependent kinase 1 and cyclin B1 expression but upregulation of p21 Waf1/Cip1, p27 Kip1, and p53 expression. ALS induced mitochondria-mediated apoptosis and autophagy in both AGS and NCI-N78 cells. ALS induced the expression of proapoptotic proteins but inhibited the expression of antiapoptotic proteins, with a significant increase in the release of cytochrome c and the activation of caspase 9 and caspase 3 in both cell lines. ALS induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) signaling pathways while activating the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway as indicated by their altered phosphorylation, contributing to the proautophagic effects of ALS. SB202191 and wortmannin enhanced the autophagy-inducing effect of ALS in AGS and NCI-N78 cells. Notably, ALS treatment significantly decreased the ratio of phosphorylated AURKA over AURKA, which may contribute, at least in part, to the inducing effects of ALS on cell-cycle arrest and autophagy in AGS and NCI-N78 cells. Taken together, these results indicate that ALS exerts a potent inhibitory effect on cell proliferation but inducing effects on cell-cycle arrest, mitochondria-dependent apoptosis, and autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AURKA-mediated signaling pathways in AGS and NCI-N78 cells. FAU - Yuan, Chun-Xiu AU - Yuan CX AD - Department of Oncology, General Hospital Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China ; Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA. FAU - Zhou, Zhi-Wei AU - Zhou ZW AD - Department of Pharmaceutical Science, 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, Guizhou, People's Republic of China. FAU - Yang, Yin-Xue AU - Yang YX AD - Department of Colorectal Surgery, General Hospital, Ningxia Medical University, Yinchuan, Ningxia, 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, Guiyang 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 - 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 - Yang, Tianxing AU - Yang T AD - Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA. FAU - Wang, Ning-Ju AU - Wang NJ AD - Department of Oncology, General Hospital Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China. FAU - Zhao, Ruan Jin AU - Zhao RJ AD - Center for Traditional Chinese Medicine, Sarasota, FL, USA. FAU - Zhou, Shu-Feng AU - Zhou SF AD - Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150114 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (Antineoplastic Agents) RN - 0 (Azepines) RN - 0 (MLN 8237) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) 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 - Antineoplastic Agents/*pharmacology MH - Apoptosis/*drug effects MH - Aurora Kinase A/*antagonists & inhibitors/metabolism MH - Autophagy/*drug effects MH - Azepines/*pharmacology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Dose-Response Relationship, Drug MH - G2 Phase Cell Cycle Checkpoints/drug effects MH - Humans MH - Mitosis/*drug effects MH - Phosphatidylinositol 3-Kinase/metabolism MH - Phosphorylation MH - Protein Kinase Inhibitors/*pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyrimidines/*pharmacology MH - Signal Transduction/drug effects MH - Stomach Neoplasms/*enzymology/pathology MH - TOR Serine-Threonine Kinases/metabolism MH - Time Factors MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC4298344 OTO - NOTNLM OT - AURKA OT - alisertib OT - apoptosis OT - autophagy OT - gastric cancer EDAT- 2015/01/23 06:00 MHDA- 2015/09/10 06:00 PMCR- 2015/01/14 CRDT- 2015/01/23 06:00 PHST- 2015/01/23 06:00 [entrez] PHST- 2015/01/23 06:00 [pubmed] PHST- 2015/09/10 06:00 [medline] PHST- 2015/01/14 00:00 [pmc-release] AID - dddt-9-487 [pii] AID - 10.2147/DDDT.S74127 [doi] PST - epublish SO - Drug Des Devel Ther. 2015 Jan 14;9:487-508. doi: 10.2147/DDDT.S74127. eCollection 2015.