Skip to main content

Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics.

Publication ,  Journal Article
Knecht, DA; LaFleur, RA; Kahsai, AW; Argueta, CE; Beshir, AB; Fenteany, G
Published in: PLoS One
November 24, 2010

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.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

November 24, 2010

Volume

5

Issue

11

Start / End Page

e14039

Location

United States

Related Subject Headings

  • Triterpenes
  • Polymerization
  • Peptides, Cyclic
  • Molecular Structure
  • Molecular Dynamics Simulation
  • Microscopy, Confocal
  • General Science & Technology
  • Gelsolin
  • Dose-Response Relationship, Drug
  • Dictyostelium
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Knecht, D. A., LaFleur, R. A., Kahsai, A. W., Argueta, C. E., Beshir, A. B., & Fenteany, G. (2010). Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics. PLoS One, 5(11), e14039. https://doi.org/10.1371/journal.pone.0014039
Knecht, David A., Rebecca A. LaFleur, Alem W. Kahsai, Christian E. Argueta, Anwar B. Beshir, and Gabriel Fenteany. “Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics.PLoS One 5, no. 11 (November 24, 2010): e14039. https://doi.org/10.1371/journal.pone.0014039.
Knecht DA, LaFleur RA, Kahsai AW, Argueta CE, Beshir AB, Fenteany G. Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics. PLoS One. 2010 Nov 24;5(11):e14039.
Knecht, David A., et al. “Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics.PLoS One, vol. 5, no. 11, Nov. 2010, p. e14039. Pubmed, doi:10.1371/journal.pone.0014039.
Knecht DA, LaFleur RA, Kahsai AW, Argueta CE, Beshir AB, Fenteany G. Cucurbitacin I inhibits cell motility by indirectly interfering with actin dynamics. PLoS One. 2010 Nov 24;5(11):e14039.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

November 24, 2010

Volume

5

Issue

11

Start / End Page

e14039

Location

United States

Related Subject Headings

  • Triterpenes
  • Polymerization
  • Peptides, Cyclic
  • Molecular Structure
  • Molecular Dynamics Simulation
  • Microscopy, Confocal
  • General Science & Technology
  • Gelsolin
  • Dose-Response Relationship, Drug
  • Dictyostelium