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      The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells

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          Abstract

          Numerous studies have shown that alteration of actin remodeling plays a pivotal role in the regulation of morphologic and phenotypic changes leading to malignancy. In the present study, we searched for drugs that can regulate actin polymerization and reverse the malignant phenotype in cancer cells. We developed a cell-free high-throughput screening assay for the identification of compounds that induce the actin polymerization in vitro, by fluorescence anisotropy. Then, the potential of the hit compound to restore the actin cytoskeleton and reverse the malignant phenotype was checked in EWS-Fli1-transformed fibroblasts and in B16-F10 melanoma cells. A β-carboline extracted from Peganum harmala (i.e., harmine) is identified as a stimulator of actin polymerization through a mechanism independent of actin binding and requiring intracellular factors involved in a process that regulates actin kinetics. Treatment of malignant cells with non-cytotoxic concentrations of harmine induces the recovery of a non-malignant cell morphology accompanied by reorganization of the actin cytoskeleton, rescued cell–cell adhesion, inhibition of cell motility and loss of anchorage-independent growth. In conclusion, harmine induces the reversion of the malignant phenotype by a process involving the modulation of actin dynamics and is a potential anti-tumor agent acting principally through a non-cytotoxic process.

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          Most cited references38

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          Anchorage-independent cell growth signature identifies tumors with metastatic potential.

          The oncogenic phenotype is complex, resulting from the accumulation of multiple somatic mutations that lead to the deregulation of growth regulatory and cell fate controlling activities and pathways. The ability to dissect this complexity, so as to reveal discrete aspects of the biology underlying the oncogenic phenotype, is critical to understanding the various mechanisms of disease as well as to reveal opportunities for novel therapeutic strategies. Previous work has characterized the process of anchorage-independent growth of cancer cells in vitro as a key aspect of the tumor phenotype, particularly with respect to metastatic potential. Nevertheless, it remains a major challenge to translate these cell biology findings into the context of human tumors. We previously used DNA microarray assays to develop expression signatures, which have the capacity to identify subtle distinctions in biological states and can be used to connect in vitro and in vivo states. Here we describe the development of a signature of anchorage-independent growth, show that the signature exhibits characteristics of deregulated mitochondrial function and then demonstrate that the signature identifies human tumors with the potential for metastasis.
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            Actin and actin-binding proteins. A critical evaluation of mechanisms and functions.

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              Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells

              Cell adhesions link cells to the extracellular matrix (ECM) and to each other and depend on interactions with the actin cytoskeleton. Both cell–ECM and cell–cell adhesion sites contain discrete, yet overlapping, functional modules. These modules establish physical associations with the actin cytoskeleton, locally modulate actin organization and dynamics, and trigger intracellular signaling pathways. Interplay between these modules generates distinct actin architectures that underlie different stages, types, and functions of cell–ECM and cell–cell adhesions. Actomyosin contractility is required to generate mature, stable adhesions, as well as to sense and translate the mechanical properties of the cellular environment into changes in cell organization and behavior. Here, we review the organization and function of different adhesion modules and how they interact with the actin cytoskeleton. We highlight the molecular mechanisms of mechanotransduction in adhesions and how adhesion molecules mediate cross talk between cell–ECM and cell–cell adhesion sites. Discrete multiprotein complexes called cell adhesions link cells to the extracellular matrix and to each other. They depend on interactions with the actin cytoskeleton and serve as hubs for signaling and mechanotransduction.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                08 May 2020
                May 2020
                : 9
                : 5
                : 1168
                Affiliations
                [1 ]Centre National de la Recherche Scientifique, CNRS UMR 8113, Laboratoire de Biologie et Pharmacologie Appliquée, 94230 Cachan, France; ronan.lemoigne29@ 123456gmail.com (R.L.M.); fsubra@ 123456ens-paris-saclay.fr (F.S.)
                [2 ]AC Bioscience, Innovation Park, Ecole Polytechnique Fédérale de Lausanne, CH-1024 Ecublens, Switzerland; manale.karam@ 123456ac-bioscience.com
                [3 ]Département de Biologie, École Normale Supérieure Paris-Saclay, Université Paris-Saclay, 94230 Cachan, France
                Author notes
                [†]

                Present address: Essa Pharma Inc., South San Francisco, CA 94080, USA.

                Author information
                https://orcid.org/0000-0002-5181-9468
                https://orcid.org/0000-0002-6433-4742
                Article
                cells-09-01168
                10.3390/cells9051168
                7290983
                32397195
                a85dcfda-a01a-47d2-9cd1-72403e649276
                © 2020 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 (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 April 2020
                : 06 May 2020
                Categories
                Article

                harmine,actin polymerization,cell adhesion,tumor reversion

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