PMID- 28386317
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220316
IS  - 1943-8141 (Print)
IS  - 1943-8141 (Electronic)
IS  - 1943-8141 (Linking)
VI  - 9
IP  - 3
DP  - 2017
TI  - Alisertib induces G(2)/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR- and 
      p38 MAPK-mediated pathways in human glioblastoma cells.
PG  - 845-873
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 pi-pi 
      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 G(2)/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.
FAU - Liu, Zheng
AU  - Liu Z
AD  - Department of Neurosurgery, General Hospital of Ningxia Medical 
      UniversityYinchuan, Ningxia, China; Ningxia Key Laboratory of Cerebrocranial 
      Disease, Incubation Base of National Key Laboratory, Ningxia Medical 
      UniversityYinchuan, Ningxia, China; Department of Pharmaceutical Sciences, 
      College of Pharmacy, University of South FloridaTampa, FL, USA.
FAU - Wang, Feng
AU  - Wang F
AD  - Department of Neurosurgery, General Hospital of Ningxia Medical 
      UniversityYinchuan, Ningxia, China; Ningxia Key Laboratory of Cerebrocranial 
      Disease, Incubation Base of National Key Laboratory, Ningxia Medical 
      UniversityYinchuan, Ningxia, China.
FAU - Zhou, Zhi-Wei
AU  - Zhou ZW
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of South 
      Florida Tampa, FL, USA.
FAU - Xia, He-Chun
AU  - Xia HC
AD  - Department of Neurosurgery, General Hospital of Ningxia Medical 
      UniversityYinchuan, Ningxia, China; Ningxia Key Laboratory of Cerebrocranial 
      Disease, Incubation Base of National Key Laboratory, Ningxia Medical 
      UniversityYinchuan, Ningxia, China.
FAU - Wang, Xin-Yu
AU  - Wang XY
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of South 
      FloridaTampa, FL, USA; Institute of Clinical Pharmacology, Department of 
      Pharmacy, General Hospital of Ningxia Medical UniversityYinchuan, Ningxia, China.
FAU - Yang, Yin-Xue
AU  - Yang YX
AD  - Department of Colorectal Surgery, General Hospital of Ningxia Medical University 
      Yinchuan, Ningxia, China.
FAU - He, Zhi-Xu
AU  - He ZX
AD  - Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue 
      Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, 
      Laboratory Animal Center, Guizhou Medical University Guiyang, China.
FAU - Sun, Tao
AU  - Sun T
AD  - Department of Neurosurgery, General Hospital of Ningxia Medical 
      UniversityYinchuan, Ningxia, China; Ningxia Key Laboratory of Cerebrocranial 
      Disease, Incubation Base of National Key Laboratory, Ningxia Medical 
      UniversityYinchuan, Ningxia, China.
FAU - Zhou, Shu-Feng
AU  - Zhou SF
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of South 
      FloridaTampa, FL, USA; Department of Bioengineering and Biotechnology, College of 
      Chemical Engineering, Huaqiao UniversityXiamen, Fujian, China.
LA  - eng
PT  - Journal Article
DEP - 20170315
PL  - United States
TA  - Am J Transl Res
JT  - American journal of translational research
JID - 101493030
PMC - PMC5375982
OTO - NOTNLM
OT  - DAOY cell
OT  - Glioblastoma
OT  - PI3K/Akt/mTOR pathway
OT  - alisertib
OT  - apoptosis
OT  - aurora kinase A
OT  - aurora kinase B
OT  - autophagy
OT  - cell cycle
OT  - hydrogen bond
OT  - molecular docking
EDAT- 2017/04/08 06:00
MHDA- 2017/04/08 06:01
PMCR- 2017/03/15
CRDT- 2017/04/08 06:00
PHST- 2016/10/19 00:00 [received]
PHST- 2017/02/09 00:00 [accepted]
PHST- 2017/04/08 06:00 [entrez]
PHST- 2017/04/08 06:00 [pubmed]
PHST- 2017/04/08 06:01 [medline]
PHST- 2017/03/15 00:00 [pmc-release]
PST - epublish
SO  - Am J Transl Res. 2017 Mar 15;9(3):845-873. eCollection 2017.