title: 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.
abstract: 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.
authors.affiliation: Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.affiliation: Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors.forename: Yin-Xue
authors.initials: YX
authors.lastname: Yang
authors.affiliation: Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
authors.forename: Qi-Lun
authors.initials: QL
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China ; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Pan
authors.affiliation: Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.
authors.forename: Zhi-Xu
authors.initials: ZX
authors.lastname: He
authors.affiliation: Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People's Republic of China.
authors.forename: Xueji
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, People's Republic of China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.
authors.forename: Jia-Xuan
authors.initials: JX
authors.lastname: Qiu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: ALS; apoptosis; autophagy; breast cancer; cell cycle; p38 MAPK
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