Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Naydenov, Nayden G.; Lechuga, Susana; Huang, Emina H.; Ivanov, Andrei I.

doi:10.3390/cancers13040741

Cited by 20 publications

(16 citation statements)

References 192 publications

(353 reference statements)

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“…Depletion of this chaperone was shown to inhibit motility of breast and ovarian cancer cells 27,29 , but promoted migration of osteosarcoma and melanoma cells 30,67 . This resembles the reported opposite effects of NM-II inhibition on cell migration under different experimental conditions 52,68 and may reflect complex regulatory effects of UNC-45A-driven myofilament assembly in motile cells. We observed that loss of UNC-45A inhibited both collective migration of IEC sheets and individual cell passage through membrane pores (Fig.…”

Section: Discussionsupporting

confidence: 82%

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair

Lechuga

Cartagena‐Rivera

Khan

et al. 2021

Preprint

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The actomyosin cytoskeleton serves as a key regulator of the integrity and remodeling of epithelial barriers by controlling assembly and functions of intercellular junctions and cell-matrix adhesions. While biochemical mechanisms that regulate activity of non-muscle myosin II (NM-II) in epithelial cells have been extensively investigated, little is known about assembly of the contractile myosin structures at the epithelial adhesion sites. UNC-45A is a cytoskeletal chaperone that is essential for proper folding of NM II heavy chains and myofilament assembly. We found abundant expression of UNC-45A in human intestinal epithelial cell (IEC) lines and in the epithelial layer of the normal human colon. Interestingly, protein levels of UNC-45A were decreased in colonic epithelium of patients with ulcerative colitis. CRISPR/Cas9-mediated knock-out of UNC-45A in HT-29 and SK-CO15 IEC disrupted epithelial barrier integrity, impaired assembly of epithelial adherence and tight junctions and attenuated cell migration. Consistently, decreased UNC-45 expression increased permeability of the Drosophila gut in vivo. The mechanisms underlying barrier disruptive and anti-migratory effects of UNC-45A depletion involved disorganization of the actomyosin bundles at epithelial junctions and the migrating cell edge. Loss of UNC-45A also decreased contractile forces at epithelial junctions and matrix adhesions. Expression of deletion mutants revealed roles for the myosin binding domain of UNC-45A in controlling IEC junctions and motility. Our findings uncover a novel mechanism that regulates integrity and restitution of the intestinal epithelial barrier, which may be impaired during mucosal inflammation.

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Section: Discussionsupporting

confidence: 82%

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair

Lechuga

Cartagena‐Rivera

Khan

et al. 2021

Preprint

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“…Cells have other modes of migration that are unique to 3D culture such as bleb-based amoeboid migration which typically does not require protrusions 44 , 45 . Actomyosin regulation in 3D has been extensively studied in other cancer types, such as breast and colorectal cancer 17 , 44 , 46 . In the context of liver cancer, while some chemical inhibitors may be able to stop invasive phenotypes on 2D surfaces, they may not be effective in stopping 3D migration.…”

Section: Discussionmentioning

confidence: 99%

Cytoskeletal dynamics regulates stromal invasion behavior of distinct liver cancer subtypes

et al. 2022

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Drug treatment against liver cancer has limited efficacy due to heterogeneous response among liver cancer subtypes. In addition, the functional biophysical phenotypes which arise from this heterogeneity and contribute to aggressive invasive behavior remain poorly understood. This study interrogated how heterogeneity in liver cancer subtypes contributes to differences in invasive phenotypes and drug response. Utilizing histological analysis, quantitative 2D invasion metrics, reconstituted 3D hydrogels, and bioinformatics, our study linked cytoskeletal dynamics to differential invasion profiles and drug resistance in liver cancer subtypes. We investigated cytoskeletal regulation in 2D and 3D culture environments using two liver cancer cell lines, SNU-475 and HepG2, chosen for their distinct cytoskeletal features and invasion profiles. For SNU-475 cells, a model for aggressive liver cancer, many cytoskeletal inhibitors abrogated 2D migration but only some suppressed 3D migration. For HepG2 cells, cytoskeletal inhibition did not significantly affect 3D migration but did affect proliferative capabilities and spheroid core growth. This study highlights cytoskeleton driven phenotypic variation, their consequences and coexistence within the same tumor, as well as efficacy of targeting biophysical phenotypes that may be masked in traditional screens against tumor growth.

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“…NMMII and PM-smACSK could be a signaling hub linking execution of cell proliferation, migration and apoptosis to signaling pathways controlling activities of ion channels and transporters. NMMII isoforms appear to regulate the metastatic potential of cancer cells and, thus, to be novel therapeutic targets [ 150 , 151 , 152 ]. Our hypothesis on NMMII as a key player in cell volume sensing broadens the spectrum of effects of NMMII in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Two Motors and One Spring: Hypothetic Roles of Non-Muscle Myosin II and Submembrane Actin-Based Cytoskeleton in Cell Volume Sensing

Barvitenko¹,

Aslam

Lawen

et al. 2021

IJMS

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Changes in plasma membrane curvature and intracellular ionic strength are two key features of cell volume perturbations. In this hypothesis we present a model of the responsible molecular apparatus which is assembled of two molecular motors [non-muscle myosin II (NMMII) and protrusive actin polymerization], a spring [a complex between the plasma membrane (PM) and the submembrane actin-based cytoskeleton (smACSK) which behaves like a viscoelastic solid] and the associated signaling proteins. We hypothesize that this apparatus senses changes in both the plasma membrane curvature and the ionic strength and in turn activates signaling pathways responsible for regulatory volume increase (RVI) and regulatory volume decrease (RVD). During cell volume changes hydrostatic pressure (HP) changes drive alterations in the cell membrane curvature. HP difference has opposite directions in swelling versus shrinkage, thus allowing distinction between them. By analogy with actomyosin contractility that appears to sense stiffness of the extracellular matrix we propose that NMMII and actin polymerization can actively probe the transmembrane gradient in HP. Furthermore, NMMII and protein-protein interactions in the actin cortex are sensitive to ionic strength. Emerging data on direct binding to and regulating activities of transmembrane mechanosensors by NMMII and actin cortex provide routes for signal transduction from transmembrane mechanosensors to cell volume regulatory mechanisms.

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Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Cited by 20 publications

References 192 publications

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair

Cytoskeletal dynamics regulates stromal invasion behavior of distinct liver cancer subtypes

Two Motors and One Spring: Hypothetic Roles of Non-Muscle Myosin II and Submembrane Actin-Based Cytoskeleton in Cell Volume Sensing

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