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Targeting the Cytoskeleton Against Metastatic Dissemination Carmen Ruggiero, Enzo Lalli

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Targeting the Cytoskeleton Against Metastatic Dissemination Carmen Ruggiero, Enzo Lalli Targeting the cytoskeleton against metastatic dissemination Carmen Ruggiero, Enzo Lalli To cite this version: Carmen Ruggiero, Enzo Lalli. Targeting the cytoskeleton against metastatic dissemination. 2020. hal-03021468 HAL Id: hal-03021468 https://hal.archives-ouvertes.fr/hal-03021468 Preprint submitted on 24 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Cancer and Metastasis Reviews https://doi.org/10.1007/s10555-020-09936-0 NON-THEMATIC REVIEW Targeting the cytoskeleton against metastatic dissemination Carmen Ruggiero1,2 & Enzo Lalli2,3 Received: 19 September 2020 /Accepted: 8 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Cancer is a pathology characterized by a loss or a perturbation of a number of typical features of normal cell behaviour. Indeed, the acquisition of an inappropriate migratory and invasive phenotype has been reported to be one of the hallmarks of cancer. The cytoskeleton is a complex dynamic network of highly ordered interlinking filaments playing a key role in the control of fundamental cellular processes, like cell shape maintenance, motility, division and intracellular transport. Moreover, deregulation of this complex machinery contributes to cancer progression and malignancy, enabling cells to acquire an invasive and metastatic phenotype. Metastasis accounts for 90% of death from patients affected by solid tumours, while an efficient prevention and suppression of metastatic disease still remains elusive. This results in the lack of effective therapeutic options currently available for patients with advanced disease. In this context, the cytoskeleton with its regulatory and structural proteins emerges as a novel and highly effective target to be exploited for a substantial therapeutic effort toward the development of specific anti-metastatic drugs. Here we provide an overview of the role of cytoskeleton components and interacting proteins in cancer metastasis with a special focus on small molecule compounds interfering with the actin cytoskeleton organization and function. The emerging involvement of microtubules and intermediate filaments in cancer metastasis is also reviewed. Keywords Cytoskeleton . Migration . Invasion . Cancer metastasis . Small molecule compounds . Anti-metastatic drugs 1 Introduction key cellular events like cellular movement, cell division and intracellular transport. Several proteins belonging to/ Metastasis, which is defined as the dissemination of cancer interacting with the cell cytoskeleton are mutated or abnor- cells from a primary tumour to a distant organ, represents mally expressed under pathological conditions, significantly the most difficult problem in cancer treatment and is the main affecting the invasive and metastatic phenotype of tumour cause of death of cancer patients [1]. The essential prerequisite cells [2, 3]. These findings pinpoint the cytoskeleton as an for cancer cells to metastasize is the dramatic reorganizationAPPROVAL of important provider of potential therapeutic targets against met- their cytoskeleton. Under physiological conditions the three astatic dissemination. We review here the actin cytoskeleton components of the cytoskeleton, microfilaments (MFs), mi- proteins implicated in cancer metastasis and the drugs devel- crotubules (MTs) and intermediate filaments (IFs) collectively oped so far to interfere with their signalling/function or with provide and maintain cell structure and shape and orchestrate the polymerization and contractility of the actin cytoskeleton. The emerging role of MTs and IFs in cancer metastasis is also discussed. * Carmen Ruggiero [email protected] 2 Cytoskeleton components and function 1 Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d’Azur, CNRS, 660 route des Lucioles-Sophia Antipolis, 06560 Valbonne, France The cytoskeleton is a complex, dynamic network of highly “ ” 2 NEOGENEX-CANCER CNRS International Associated ordered interlinking filaments forming the infrastructure of Laboratory, 660 route des Lucioles, Sophia Antipolis, eukaryotic and prokaryotic cells [4]. In eukaryotic cells the 06560 Valbonne, France cytoskeleton consists of a complex mesh of protein filaments 3 Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, 660 and motor proteins, which regulate a variety of important cel- route des Lucioles - Sophia Antipolis, 06560 Valbonne, France lular functions. Among them, the cytoskeleton supports cell Cancer Metastasis Rev shape maintenance, it holds organelles in place and it provides muscle α-actin, and the smooth muscle α-andγ-actins the cell with the mechanical support to carry out essential [39–41]. MFs are assembled through the polymerization of processes like division, cytokinesis, motility, intracellular G-actin monomers into F-actin polymers. This process is transport and organization of the organelles within the cell highly dependent upon the concentration of free actin mono- [5–8]. Three different types of protein filaments compose the mers, which subsequently drives the equilibrium toward po- cytoskeleton: MFs, MTs and Ifs (Table 1). Those fibres differ lymerization that is regulated also by a series of actin-associ- in their size, with MTs being the thickest and MFs being the ated proteins [42]. It is the case, for example, of profilin [43, finest. A description of each is reported below. 44] that binds to monomeric actin thereby occupying an actin- Concerning the cytoskeletal motor proteins, three super- actin contact site. Once bound, profilin sequesters actin from families are known: myosins, kinesins and dyneins [36]. the pool of polymerizable “free” monomers, thus impairing Myosin motors act upon actin filaments to generate cell sur- polymerization. G-actin binds ATP, which is hydrolyzed to face contractions as well as vesicle motility, cytoplasmic ADP shortly after incorporation in the growing filament [45, streaming and muscle cell contraction [37]. The kinesin and 46]. Actin filaments display an inert minus end and a growing dynein MT–based motors move vesicles and organelles with- plus end to which new monomers are added. Generally, the in the cells, cause the beating of cilia and flagella and partic- plus terminus is oriented toward the cell surface. The rapid ipate within the mitotic and meiotic spindles to the segregation addition of monomers onto that end promotes the formation of of replicated chromosomes [25, 38]. actin surface protrusions for cell migration [17]. Various fac- tors like calcium, ATP, cAMP and actin-binding proteins have 2.1 Microfilaments been described to regulate the rate of actin polymerization. MFs are often subjected to “treadmilling”,suchthatmono- MFs are made of actin polymers and a variety of actin-binding mers are continuously added to the plus end and removed proteins (ABPs). Indeed, in cells actin exists either as a mono- from the minus end while the filament maintains the same mer (globular, G-actin) or as a polymer (filamentous, F-actin). overall length [9–11]. Actin filaments are present in all cells; Monomeric actin that has a molecular weight of approximate- however, their proportion is different depending on the cell ly 42 kDa is expressed in all eukaryotic cells and is highly type. The most abundant and organized system of MFs are conserved throughout evolution. Indeed, six isoforms of actin striated muscle cells. MFs are ordered and organized by a have been described in mammals: the cytoskeletal and cyto- number of ABPs within the cytoplasm and on the surface of plasmic β-andγ-actins, cardiac muscle α-actin, skeletal cell membranes [12]. Those proteins have different functions Table 1 Cytoskeleton components Structure/composition Diameter Main functions Microfilaments Twisted double strands of actin, each a polymer of actin monomers, 7 nm Cell division (cleavage furrow formation) [13] – associated to a series of actin-binding proteins [9 12] Maintenance of (tension-bearing elements) and changes in cell shape [5, 6] APPROVAL– Muscle contraction [14 16] Cell movement/migration [5, 17–24] Intracellular transport of organelles [5, 25] Microtubules 13 linear protofilaments assembled around a hollow core and arranged 25 nm Maintenance of cell shape by resisting tension in parallel, composed of a single type of the globular protein tubulin, (compression-resisting “girders”)[6] α β which is a dimer of 2 closely related polypeptides, -and -tubulin Separation of chromosomes during mitosis [8, [26] 27–30] Intracellular transport of organelles [25, 31] Establishment of cell polarity [32] FOR Cell motility (as in cilia et flagella) [22] Intermediate Helical subunits of fibrous proteins (varying with function and cell 8–10 nm Supply of mechanical strength and support filaments type) supercoiled into thicker cables [33] necessary to reinforce cells and organize them into tissues [34] Anchoring of the nucleus and some organelles within the cytoplasm and nuclear lamina formation [35] Maintenance of cell shape (tension-bearing elements) [6] Cancer Metastasis Rev and act on MFs
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