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      Cucurbitacin E Inhibits Proliferation and Migration of Intestinal Epithelial Cells via Activating Cofilin

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          Abstract

          The proliferation and migration of intestinal epithelial cell is important to the barrier integrity of intestinal epithelium. Cucurbitacin E (CuE) is one of the tetracyclic triterpenoids extracted from the cucurbitaceae that has been shown to inhibit cancer cell growth, tumor angiogenesis and inflammatory response. Nevertheless, the role of Cucurbitacin E in regulating the proliferation and migration of intestinal epithelial cells remain unclear. In this study, the human intestinal epithelial cell line Caco-2 was treated with CuE and the effects of CuE on cell cycle, proliferation, migration and actin dynamics in Caco-2 cells were investigated successively. We found that CuE significantly inhibited the cell proliferation and migration, inducing the cell cycle arrest in G2/M phase and disrupting the actin dynamic balance in Caco-2 cells. Finally, we showed that CuE inhibited cofilin phosphorylation by suppressing the phosphorylation of both LIM kinase (LIMK)1 and LIMK2 in vitro, resulting in the activation of cofilin, which is closely associated with cell proliferation and migration. Therefore, our studies provided the first evidence that CuE inhibited the proliferation and migration of intestinal epithelial cells via activating cofilin, and CuE is a potential candidate in intestinal disease therapy.

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          Most cited references32

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          Cofilin promotes actin polymerization and defines the direction of cell motility.

          A general caging method for proteins that are regulated by phosphorylation was used to study the in vivo biochemical action of cofilin and the subsequent cellular response. By acute and local activation of a chemically engineered, light-sensitive phosphocofilin mimic, we demonstrate that cofilin polymerizes actin, generates protrusions, and determines the direction of cell migration. We propose a role for cofilin that is distinct from its role as an actin-depolymerizing factor.
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            Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation.

            Cofilin and actin-depolymerizing factor (ADF) are actin-binding proteins that play an essential role in regulating actin filament dynamics and reorganization by stimulating the severance and depolymerization of actin filaments. Cofilin/ADF are inactivated by phosphorylation at the serine residue at position 3 by LIM-kinases (LIMKs) and testicular protein kinases (TESKs) and are reactivated by dephosphorylation by the slingshot (SSH) family of protein phosphatases and chronophin. This review describes recent advances in our understanding of the signaling mechanisms regulating LIMKs and SSHs and the functional roles of cofilin phospho-regulation in cell migration, tumor invasion, mitosis, neuronal development, and synaptic plasticity. Accumulating evidence demonstrates that the phospho-regulation of cofilin/ADF is a key convergence point of cell signaling networks that link extracellular stimuli to actin cytoskeletal dynamics and that spatiotemporal control of cofilin/ADF activity by LIMKs and SSHs plays a crucial role in a diverse array of cellular and physiological processes. Perturbations in the normal control of cofilin/ADF activity underlie many pathological conditions, including cancer metastasis and neurological and cardiovascular disorders. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Cofilin phosphatases and regulation of actin dynamics.

              Cofilin is a ubiquitous actin-binding factor required for the reorganization of actin filaments in eukaryotes. The dephosphorylation of cofilin enables its actin severing and depolymerizing activity and drives directional cell motility, thus providing a simple phosphoregulatory mechanism for actin reorganization. To date, two cofilin-specific phosphatases have been identified: Slingshot and Chronophin. These cofilin phosphatases are unrelated in sequence and regulatory properties, each potentially providing a unique mechanism for cofilin activation under varying biological circumstances.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                07 August 2018
                2018
                : 9
                : 1090
                Affiliations
                [1] 1State Key Laboratory of Trauma, Burns, and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
                [2] 2Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
                Author notes

                Edited by: Marco Falasca, Curtin University, Australia

                Reviewed by: Elena Monica Borroni, Humanitas Research Hospital, Italy; Khyati Shah, University of California, San Francisco, United States

                *Correspondence: Fengjun Wang, wangfj@ 123456tmmu.edu.cn

                These authors have contributed equally to this work

                This article was submitted to Gastrointestinal Sciences, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.01090
                6090878
                02ab3f78-14af-45da-8605-ce18e0213332
                Copyright © 2018 Song, Wang, Li, Sui, Wang and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 April 2018
                : 23 July 2018
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 38, Pages: 9, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81272087
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                cucurbitacin e,cofilin,intestinal epithelial cells,cell cycle,cell proliferation,cell migration,actin,lim kinase

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