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Inhibition of mitotic Aurora kinase A by alisertib induces apoptosis and autophagy of human gastric cancer AGS and NCI-N78 cells.
- Source :
-
Drug design, development and therapy [Drug Des Devel Ther] 2015 Jan 14; Vol. 9, pp. 487-508. Date of Electronic Publication: 2015 Jan 14 (Print Publication: 2015). - Publication Year :
- 2015
-
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.
- Subjects :
- Aurora Kinase A metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Dose-Response Relationship, Drug
G2 Phase Cell Cycle Checkpoints drug effects
Humans
Phosphatidylinositol 3-Kinase metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction drug effects
Stomach Neoplasms pathology
TOR Serine-Threonine Kinases metabolism
Time Factors
p38 Mitogen-Activated Protein Kinases metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
Aurora Kinase A antagonists & inhibitors
Autophagy drug effects
Azepines pharmacology
Mitosis drug effects
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Stomach Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1177-8881
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- Drug design, development and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 25609923
- Full Text :
- https://doi.org/10.2147/DDDT.S74127