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The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell
cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling
pathways in human breast cancer cells
#MMPMID25834401
Li JP
; Yang YX
; Liu QL
; Pan ST
; He ZX
; Zhang X
; Yang T
; Chen XW
; Wang D
; Qiu JX
; Zhou SF
Drug Des Devel Ther
2015[]; 9
(?): 1627-52
PMID25834401
show ga
Alisertib (ALS) is an investigational potent Aurora A kinase inhibitor currently
undergoing clinical trials for the treatment of hematological and
non-hematological malignancies. However, its antitumor activity has not been
tested in human breast cancer. This study aimed to investigate the effect of ALS
on the growth, apoptosis, and autophagy, and the underlying mechanisms in human
breast cancer MCF7 and MDA-MB-231 cells. In the current study, we identified that
ALS had potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects in
MCF7 and MDA-MB-231 cells. ALS arrested the cells in G2/M phase in MCF7 and
MDA-MB-231 cells which was accompanied by the downregulation of cyclin-dependent
kinase (CDK)1/cell division cycle (CDC) 2, CDK2, and cyclin B1 and upregulation
of p21 Waf1/Cip1, p27 Kip1, and p53, suggesting that ALS induces G2/M arrest
through modulation of p53/p21/CDC2/cyclin B1 pathways. ALS induced
mitochondria-mediated apoptosis in MCF7 and MDA-MB-231 cells; ALS significantly
decreased the expression of B-cell lymphoma 2 (Bcl-2), but increased the
expression of B-cell lymphoma 2-associated X protein (Bax) and p53-upregulated
modulator of apoptosis (PUMA), and increased the expression of cleaved caspases 3
and 9. ALS significantly increased the expression level of membrane-bound
microtubule-associated protein 1 light chain 3 (LC3)-II and beclin 1 and induced
inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B
(Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein
kinase (MAPK) pathways in MCF7 and MDA-MB-231 cells as indicated by their altered
phosphorylation, contributing to the pro-autophagic activities of ALS.
Furthermore, treatment with wortmannin markedly downregulated ALS-induced p38
MAPK activation and LC3 conversion. In addition, knockdown of the p38 MAPK gene
by ribonucleic acid interference upregulated Akt activation and resulted in
LC3-II accumulation. These findings indicate that ALS promotes cellular apoptosis
and autophagy in breast cancer cells via modulation of p38 MAPK/Akt/mTOR
pathways. Further studies are warranted to further explore the molecular targets
of ALS in the treatment of breast cancer.
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