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The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells

Li, Jin-Ping, Yang, Yin-Xue, Liu, Qi-Lun, Zhou, Zhi-Wei, Pan, Shu-Ting, He, Zhi-Xu, Zhang, Xueji, Yang, Tianxin, Pan, Si-Yuan, Duan, Wei, He, Shu-Ming, Chen, Xiao-Wu, Qiu, Jia-Xuan and Zhou, Shu-Feng 2015, The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells, Drug design, development and therapy, vol. 9, pp. 1027-1062, doi: 10.2147/DDDT.S74412.

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Title The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells
Author(s) Li, Jin-Ping
Yang, Yin-Xue
Liu, Qi-Lun
Zhou, Zhi-Wei
Pan, Shu-Ting
He, Zhi-Xu
Zhang, Xueji
Yang, Tianxin
Pan, Si-Yuan
Duan, WeiORCID iD for Duan, Wei orcid.org/0000-0001-5782-9184
He, Shu-Ming
Chen, Xiao-Wu
Qiu, Jia-Xuan
Zhou, Shu-Feng
Journal name Drug design, development and therapy
Volume number 9
Start page 1027
End page 1062
Publisher Dove Medical Press
Place of publication Macclesfield, Eng.
Publication date 2015
ISSN 1177-8881
Keyword(s) Danusertib
EMT
apoptosis
autophagy
breast cancer
cell cycle
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
MOLECULAR-MECHANISMS
PANCREATIC-CANCER
IN-VITRO
DEATH
TARGETS
GROWTH
DEGRADATION
PHA-739358
ACTIVATION
SPINDLE
Summary Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.
Language eng
DOI 10.2147/DDDT.S74412
Field of Research 111501 Basic Pharmacology
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, Dove Medical Press
Persistent URL http://hdl.handle.net/10536/DRO/DU:30073294

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.