Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics

Autor: David A Knecht, Rebecca A LaFleur, Alem W Kahsai, Christian E Argueta, Anwar B Beshir, Gabriel Fenteany
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Motility
lcsh:Medicine
Antineoplastic Agents
macromolecular substances
Molecular Dynamics Simulation
Biology
Peptides
Cyclic
Cell Biology/Cell Signaling
Cell Line
Polymerization
03 medical and health sciences
0302 clinical medicine
Cell Movement
Cell Biology/Cytoskeleton
Cell Line
Tumor
Depsipeptides
Animals
Dictyostelium
Cytoskeleton
STAT3
lcsh:Science
Cell Biology/Chemical Biology of the Cell
Gelsolin
Actin
030304 developmental biology
0303 health sciences
Microscopy
Confocal
Multidisciplinary
Janus kinase 2
Dose-Response Relationship
Drug
Molecular Structure
lcsh:R
food and beverages
Actin remodeling
Chemical Biology/Chemical Biology of the Cell
Actin cytoskeleton
Actins
Triterpenes
Cell biology
Actin Cytoskeleton
Actin Depolymerizing Factors
030220 oncology & carcinogenesis
biology.protein
STAT protein
lcsh:Q
Research Article
Zdroj: PLoS ONE, Vol 5, Iss 11, p e14039 (2010)
PLoS ONE
ISSN: 1932-6203
Popis: Background Cucurbitacins are plant natural products that inhibit activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway by an unknown mechanism. They are also known to cause changes in the organization of the actin cytoskeleton. Methodology/Principal Findings We show that cucurbitacin I potently inhibits the migration of Madin-Darby canine kidney (MDCK) cell sheets during wound closure, as well as the random motility of B16-F1 mouse melanoma cells, but has no effect on movement of Dictyostelium discoideum amoebae. Upon treatment of MDCK or B16-F1 cells with cucurbitacin I, there is a very rapid cessation of motility and gradual accumulation of filamentous actin aggregates. The cellular effect of the compound is similar to that observed when cells are treated with the actin filament-stabilizing agent jasplakinolide. However, we found that, unlike jasplakinolide or phallacidin, cucurbitacin I does not directly stabilize actin filaments. In in vitro actin depolymerization experiments, cucurbitacin I had no effect on the rate of actin filament disassembly at the nanomolar concentrations that inhibit cell migration. At elevated concentrations, the depolymerization rate was also unaffected, although there was a delay in the initiation of depolymerization. Therefore, cucurbitacin I targets some factor involved in cellular actin dynamics other than actin itself. Two candidate proteins that play roles in actin depolymerization are the actin-severing proteins cofilin and gelsolin. Cucurbitacin I possesses electrophilic reactivity that may lead to chemical modification of its target protein, as suggested by structure-activity relationship data. However, mass spectrometry revealed no evidence for modification of purified cofilin or gelsolin by cucurbitacin I. Conclusions/Significance Cucurbitacin I results in accumulation of actin filaments in cells by a unique indirect mechanism. Furthermore, the proximal target of cucurbitacin I relevant to cell migration is unlikely to be the same one involved in activation of the JAK2/STAT3 pathway.
Databáze: OpenAIRE
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