A Non-Antibacterial Oxazolidinone Derivative that Inhibits Epithelial Cell Sheet Migration

Henry, Kevin T. Mc; Ankala, Sudha V.; Ghosh, Arun K.; Fenteany, Gabriel

doi:10.1002/1439-7633(20021104)3:11<1105::aid-cbic1105>3.0.co;2-s

Cited by 45 publications

(48 citation statements)

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“…Researchers have screened thousands of compounds for the ability to inhibit cell migration, in hopes of developing new drug targets. 54,55 However, commonly used assays that study these interactions cannot distinguish off-target effects. For example, adding formaldehyde to cells would surely halt their cell migration, but will do so by fixing and killing the cells, not because it is a specific inhibitor of migration.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Migration of isogenic cell lines quantified by dynamic multivariate analysis of single-cell motility

Harris

Kim

Weidow

et al. 2008

Cell Adhesion & Migration

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Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Migration of isogenic cell lines quantified by dynamic multivariate analysis of single-cell motility

Harris

Kim

Weidow

et al. 2008

Cell Adhesion & Migration

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“…Images were analyzed using the public domain ImageJ program (developed at the National Institutes of Health and available on the Internet at http://rsb.info.nih.gov/ij/) on an Apple Power Macintosh computer. Progress of wound closure was quantitated from digital images by tracing the margin perimeter and determining remaining open wound area as a function of time, as previously described (McHenry et al, 2002). Following each experiment, cell viability was confirmed by the Trypan Blue dye exclusion assay.…”

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confidence: 99%

Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement

Farooqui

Fenteany

2005

Journal of Cell Science

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373

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The mechanism by which epithelial, endothelial and other strongly cell-cell adhesive cells migrate collectively as continuous sheets is not clear, even though this process is crucial for embryonic development and tissue repair in virtually all multicellular animals. Wound closure in Madin-Darby canine kidney (MDCK) epithelial cell monolayers involves Rac GTPase-dependent migration of cells both at and behind the wound edge. We report here for the first time that cells behind the margin of wounded MDCK cell monolayers, even hundreds of microns from the edge, extend `cryptic' lamellipodia against the substratum beneath cells in front of them, toward the wound, as determined by confocal, two-photon and transmission electron microscopy. These so-called submarginal cells nevertheless strictly maintain their more apical cell-cell contacts when they migrate as part of a coherent cell sheet, hiding their basal protrusions from conventional microscopy. The submarginal protrusions display the hallmarks of traditional lamellipodia based on morphology and dynamics. Cells behind the margin therefore actively crawl, instead of just moving passively when cells at the margin pull on them. The rate of migration is inversely proportional to the distance from the margin, and cells move co-ordinately, yet still in part autonomously, toward the wound area. We also clarify the ancillary role played by nonprotrusive contractile actin bundles that assemble in a Rho GTPase-dependent manner at the margin after wounding. In addition, some cell proliferation occurs at a delay after wounding but does not contribute to closure. Instead, it apparently serves to replace damaged cells so that intact spread cells can revert to their normal cuboidal morphology and the original cell density of the unbroken sheet can be restored.

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“…Early passages of cells thawed from frozen stock cultures were used in all experiments. Wound closure experiments were conducted and analyzed as described previously (15). Images taken as a function of time postwounding were imported into ImageJ for morphometric analyses.…”

Section: Methodsmentioning

confidence: 99%

“…We have exploited the classical scratch-wound closure assay for screening chemical * This work was supported, in whole or in part, by National Institutes of Health libraries to discover new compounds that inhibit or accelerate cell migration. We have identified a number of new inhibitors of cell migration, including locostatin (15)(16)(17) and the tetrahydroisoquinoline DX-52-1, a semisynthetic derivative of quinocarmycin (also known as quinocarcin) (18). These small molecules target Raf kinase inhibitor protein (16) and the membrane-actin cytoskeleton linker protein radixin (18), respectively.…”

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confidence: 99%

Analogs of Tetrahydroisoquinoline Natural Products That Inhibit Cell Migration and Target Galectin-3 Outside of Its Carbohydrate-binding Site

Kahsai

Cui

Kaniskan

et al. 2008

Journal of Biological Chemistry

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Cell migration is central to a number of normal and disease processes. Small organic molecules that inhibit cell migration have potential as both research probes and therapeutic agents. We have identified two tetrahydroisoquinoline natural product analogs with antimigratory activities on Madin-Darby canine kidney epithelial cells: a semisynthetic derivative of quinocarmycin (also known as quinocarcin), DX-52-1, and a more complex synthetic molecule, HUK-921, related to the naphthyridinomycin family. It has been assumed that the cellular effects of reactive tetrahydroisoquinolines result from the alkylation of DNA. We have reported previously that the primary target of DX-52-1 relevant to cell migration appears to be the membranecytoskeleton linker protein radixin. Here we extend the analysis of the protein targets of DX-52-1, reporting that the multifunctional carbohydrate-binding protein galectin-3 is a secondary target of DX-52-1 that may also be relevant to the antimigratory effects of both DX-52-1 and HUK-921. All known inhibitors of galectin-3 target its ␤-galactoside-binding site in the carbohydrate recognition domain. However, we found that DX-52-1 and HUK-921 bind galectin-3 outside of its ␤-galactoside-binding site. Intriguingly HUK-921, although a less potent inhibitor of cell migration than DX-52-1, had far greater selectivity for galectin-3 over radixin, exhibiting little binding to radixin, both in vitro and in cells. Overexpression of galectin-3 in cells led to a dramatic increase in cell adhesion on different extracellular matrix substrata as well as changes in cell-cell adhesion and cell motility. Galectin-3-overexpressing cells had greatly reduced sensitivity to DX-52-1 and HUK-921, and these compounds caused a change in localization of the overexpressed galectin-3 and reversion of the cells to a more normal morphology. The converse manipulation, RNA interference-based silencing of galectin-3 expression, resulted in reduced cell-matrix adhesion and cell migration. In aggregate, the data suggest that DX-52-1 and HUK-921 inhibit a carbohydrate binding-independent function of galectin-3 that is involved in cell migration.

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A Non-Antibacterial Oxazolidinone Derivative that Inhibits Epithelial Cell Sheet Migration

Cited by 45 publications

References 0 publications

Migration of isogenic cell lines quantified by dynamic multivariate analysis of single-cell motility

Migration of isogenic cell lines quantified by dynamic multivariate analysis of single-cell motility

Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement

Analogs of Tetrahydroisoquinoline Natural Products That Inhibit Cell Migration and Target Galectin-3 Outside of Its Carbohydrate-binding Site

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