title: Inhibition of mitotic Aurora kinase A by alisertib induces apoptosis and autophagy of human gastric cancer AGS and NCI-N78 cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Chun-Xiu
authors.initials: CX
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.affiliation: Department of Colorectal Surgery, General Hospital, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors.forename: Yin-Xue
authors.initials: YX
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Zhi-Xu
authors.initials: ZX
authors.lastname: He
authors.affiliation: Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China.
authors.forename: Xueji
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors.forename: Tianxing
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Oncology, General Hospital Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors.forename: Ning-Ju
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: Center for Traditional Chinese Medicine, Sarasota, FL, USA.
authors.forename: Ruan Jin
authors.initials: RJ
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: AURKA; alisertib; apoptosis; autophagy; gastric cancer