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      Ophiobolin O Isolated from Aspergillus ustus Induces G1 Arrest of MCF-7 Cells through Interaction with AKT/GSK3β/Cyclin D1 Signaling


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          Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

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          Suppression of TNF-alpha-induced apoptosis by NF-kappaB.

          Tumor necrosis factor alpha (TNF-alpha) signaling gives rise to a number of events, including activation of transcription factor NF-kappaB and programmed cell death (apoptosis). Previous studies of TNF-alpha signaling have suggested that these two events occur independently. The sensitivity and kinetics of TNF-alpha-induced apoptosis are shown to be enhanced in a number of cell types expressing a dominant-negative IkappaBalpha (IkappaBalphaM). These findings suggest that a negative feedback mechanism results from TNF-alpha signaling in which NF-kappaB activation suppresses the signals for cell death.
            • Record: found
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            JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species.

            c-Jun N-terminal kinase (JNK), or stress-activated protein kinase, is an important member of the mitogen-activated protein kinase superfamily, the members of which are readily activated by many environmental stimuli. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important groups of free radicals that are capable of eliciting direct damaging effects or acting as critical intermediate signaling molecules, leading to oxidative and nitrosative stress and a series of biological consequences. Recently there has been an increasing amount of research interest focusing on the regulatory role of JNK activation in ROS-and RNS-induced cellular responses. In this review we will first summarize and discuss some recent findings regarding the signaling mechanisms of ROS-or RNS-mediated JNK activation. Second, we will talk about the role of JNK in ROS-or RNS-mediated cell death (both apoptosis and necrosis). Finally, we will analyze the emerging evidence for the involvement of ROS and RNS as mediators in tumor necrosis factor alpha-induced apoptosis. Taken together, the accumulating knowledge about the ROS/RNS-induced JNK signaling pathway has greatly advanced our understanding of the complex processes deciding the cellular responses to environmental stress.
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              A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation.

              The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate binding site used by primed substrates. Significantly, this mutation does not affect phosphorylation of "nonprimed" substrates in the Wnt-signaling pathway (Axin and beta-catenin), suggesting new approaches to design more selective GSK3 inhibitors for the treatment of diabetes.

                Author and article information

                Role: Academic Editor
                Mar Drugs
                Mar Drugs
                Marine Drugs
                16 January 2015
                January 2015
                : 13
                : 1
                : 431-443
                [1 ]Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China; E-Mails: lvcuiting961021@ 123456126.com (C.L.); sjwei8012@ 123456hotmail.com (S.W.)
                [2 ]Teaching Management Department, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China; E-Mail: wendy_yes1@ 123456sina.com
                [3 ]Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; E-Mail: sdueduzth@ 123456126.com
                [4 ]Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
                [5 ]VIP Medicine Department, Changhai Hospital, Shanghai 200433, China
                Author notes

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mails: kuihong31@ 123456whu.edu.cn (K.H.); weimingzhu@ 123456ouc.edu.cn (W.Z.); rhchen1964@ 123456sohu.com (R.C.); huangcaig@ 123456hotmail.com (C.H.); Tel./Fax: +86-27-68752442 (K.H.); +86-532-82031268 (W.Z.); +86-21-3111-6666 (R.C.); Tel.: +86-21-8187-0970 (ext. 8020) (C.H.); Fax: +86-21-6533-4344 (C.H.).
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                : 09 May 2014
                : 26 November 2014

                Pharmacology & Pharmaceutical medicine
                ophiobolin o,g1 arrest,akt/gsk3β/cyclin d1 signaling


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