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      Inhibition of mitotic Aurora kinase A by alisertib induces apoptosis and autophagy of human gastric cancer AGS and NCI-N78 cells

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          Abstract

          Gastric cancer is one of the most common cancers and responds poorly to current chemotherapy. Alisertib (ALS) is a second-generation, orally bioavailable, highly selective small-molecule inhibitor of the serine/threonine protein kinase Aurora kinase A (AURKA). ALS has been shown to have potent anticancer effects in preclinical and clinical studies, but its role in gastric cancer treatment is unclear. This study aimed to investigate the cancer cell-killing effect of ALS on gastric cancer cell lines AGS and NCI-N78, with a focus on cell proliferation, cell-cycle distribution, apoptosis, and autophagy and the mechanism of action. The results showed that ALS exhibited potent growth-inhibitory, proapoptotic, and proautophagic effects on AGS and NCI-N78 cells. ALS concentration-dependently inhibited cell proliferation and induced cell-cycle arrest at G 2/M phase in both cell lines, with a downregulation of cyclin-dependent kinase 1 and cyclin B1 expression but upregulation of p21 Waf1/Cip1, p27 Kip1, and p53 expression. ALS induced mitochondria-mediated apoptosis and autophagy in both AGS and NCI-N78 cells. ALS induced the expression of proapoptotic proteins but inhibited the expression of antiapoptotic proteins, with a significant increase in the release of cytochrome c and the activation of caspase 9 and caspase 3 in both cell lines. ALS induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) signaling pathways while activating the 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway as indicated by their altered phosphorylation, contributing to the proautophagic effects of ALS. SB202191 and wortmannin enhanced the autophagy-inducing effect of ALS in AGS and NCI-N78 cells. Notably, ALS treatment significantly decreased the ratio of phosphorylated AURKA over AURKA, which may contribute, at least in part, to the inducing effects of ALS on cell-cycle arrest and autophagy in AGS and NCI-N78 cells. Taken together, these results indicate that ALS exerts a potent inhibitory effect on cell proliferation but inducing effects on cell-cycle arrest, mitochondria-dependent apoptosis, and autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AURKA-mediated signaling pathways in AGS and NCI-N78 cells.

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          Most cited references 51

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          Mitogen-activated protein kinases in innate immunity.

          Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies--the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.
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            Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis.

             L Ouyang,  Z. Shi,  S. Zhao (2012)
            Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment. © 2012 Blackwell Publishing Ltd.
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              Forkhead box O (FoxO) transcription factors are downstream targets of the serine/threonine protein kinase B (PKB)/Akt. The Akt kinase regulates processes of cellular proliferation and survival. Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation. Emerging evidence suggests involvement of FoxOs in diverse intracellular signaling pathways with critical roles in a number of physiological as well as pathological conditions including cancer. The FoxO signaling is regulated by their interactions with other intracellular proteins as well as their post-translational modifications such as phosphorylation. FoxOs promote cell growth inhibitory and/or apoptosis signaling by either inducing expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins, stimulating expression of death receptor ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or enhancing levels of various cyclin-dependent kinase inhibitors (CDKIs). Coupled with their ability to cross-talk with p53, FoxOs represent an important class of tumor suppressors in a variety of cancers. This review summarizes our current understanding of mechanisms by which Akt and FoxOs regulate cell growth and survival that in turn offers opportunities for development of novel strategies to combat cancer. This article is part of a Special Issue entitled: P13K-AKT-FOxO axis in cancer and aging. 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                14 January 2015
                : 9
                : 487-508
                Affiliations
                [1 ]Department of Oncology, General Hospital Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
                [2 ]Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA
                [3 ]Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino–US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China
                [4 ]Department of Colorectal Surgery, General Hospital, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
                [5 ]Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China
                [6 ]Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China
                [7 ]Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA
                [8 ]Center for Traditional Chinese Medicine, Sarasota, FL, USA
                Author notes
                Correspondence: Shu-Feng Zhou, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B Downs Boulevard, MDC 30, Tampa, FL, 33612, USA, Tel +1 813 974 6276, Fax +1 813 905 9885, Email szhou@ 123456health.usf.edu
                Article
                dddt-9-487
                10.2147/DDDT.S74127
                4298344
                © 2015 Yuan et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                gastric cancer, alisertib, aurka, apoptosis, autophagy

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