TY - JOUR
T1 - Alisertib induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR-and p38 MAPK-mediated pathways in human glioblastoma cells
AU - Liu, Zheng
AU - Wang, Feng
AU - Zhou, Zhi Wei
AU - Xia, He Chun
AU - Wang, Xin Yu
AU - Yang, Yin Xue
AU - He, Zhi Xu
AU - Sun, Tao
AU - Zhou, Shu Feng
N1 - Funding Information:
The authors appreciate the financial support from the Startup Fund of the College of Pharmacy, University of South Florida, Tampa, Florida 33612, USA and from the Startup Grant of Huaqiao University, Xiamen, Fujian 361021, China.
Publisher Copyright:
© 2017, E-Century Publishing Corporation. All rights reserved.
PY - 2017
Y1 - 2017
N2 - Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS also bound key regulating proteins of cell cycle, apoptosis and autophagy, such as cyclin-dependent kinase 1 (CDK1/CDC2), CDK2, cyclin B1, p27 Kip1, p53, cytochrome C, cleaved caspase 3, Bax, Bcl-2, Bcl-xl, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 5’-adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK), beclin 1, phosphatase and tensin homolog (PTEN), and microtubule-associated protein light chain 3 (LC3). ALS exhibited potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects on DAOY cells in a concentration-dependent manner. Notably, ALS remarkably induced G2/M arrest mainlyvia regulating the expression of CDK1/CDC2, CDK2, cyclin B1, p27 Kip1, and p53 in DAOY cells. ALS significantly induced the expression of mitochondria-mediated pro-apoptotic proteins such as Baxbut inhibited the expression of anti-apoptotic proteins such as Bcl-2 and Bcl-xl, with a significant increase in the release of cytochrome C and the activation of caspases 3 and 9. ALS also induced PI3K/Akt/ mTOR and p38 MAPK signaling pathways while activating the AMPK signaling pathway. Taken together, these findings indicate that ALS exerts a potent inhibitory effect on cell proliferation and induces mitochondria-dependent apoptosis and autophagy with the involvement of PI3K/Akt/mTOR-and p38 MAPK-mediated signaling pathways in DAOY cells. ALS is a promising anticancer agent for GBM treatment.
AB - Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS also bound key regulating proteins of cell cycle, apoptosis and autophagy, such as cyclin-dependent kinase 1 (CDK1/CDC2), CDK2, cyclin B1, p27 Kip1, p53, cytochrome C, cleaved caspase 3, Bax, Bcl-2, Bcl-xl, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 5’-adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK), beclin 1, phosphatase and tensin homolog (PTEN), and microtubule-associated protein light chain 3 (LC3). ALS exhibited potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects on DAOY cells in a concentration-dependent manner. Notably, ALS remarkably induced G2/M arrest mainlyvia regulating the expression of CDK1/CDC2, CDK2, cyclin B1, p27 Kip1, and p53 in DAOY cells. ALS significantly induced the expression of mitochondria-mediated pro-apoptotic proteins such as Baxbut inhibited the expression of anti-apoptotic proteins such as Bcl-2 and Bcl-xl, with a significant increase in the release of cytochrome C and the activation of caspases 3 and 9. ALS also induced PI3K/Akt/ mTOR and p38 MAPK signaling pathways while activating the AMPK signaling pathway. Taken together, these findings indicate that ALS exerts a potent inhibitory effect on cell proliferation and induces mitochondria-dependent apoptosis and autophagy with the involvement of PI3K/Akt/mTOR-and p38 MAPK-mediated signaling pathways in DAOY cells. ALS is a promising anticancer agent for GBM treatment.
KW - Alisertib
KW - Apoptosis
KW - Aurora kinase A
KW - Aurora kinase B
KW - Autophagy
KW - Cell cycle
KW - DAOY cell
KW - Glioblastoma
KW - Hydrogen bond
KW - Molecular docking
KW - PI3K/Akt/mTOR pathway
UR - http://www.scopus.com/inward/record.url?scp=85016437357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016437357&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:85016437357
SN - 1943-8141
VL - 9
SP - 845
EP - 873
JO - American Journal of Translational Research
JF - American Journal of Translational Research
IS - 3
M1 - AJTR0042361
ER -