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Radicicol suppresses transformation and restores tropomyosin-2 expression in both ras- and MEK-transformed cells

P N Kim1, E Jonasch, B C Mosterman

  • 1Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation & Research, Bethesda, Maryland 20892-4555, USA.

Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
|November 21, 2001
PubMed

Insights

Radicicol, an antibiotic, reverses cancer cell transformation by inhibiting transcription factors activator protein (AP-1) and serum response factor (SRF). This occurs at low concentrations, independent of the Ras/Raf/MEK/ERK pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The antibiotic radicicol is known to suppress cancer cell transformation.
  • Its antineoplastic effects were previously attributed to Raf degradation and inhibition of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway.

Purpose of the Study:

  • To investigate the precise mechanisms by which radicicol suppresses the transformed cell phenotype.
  • To determine if the Ras/Raf/MEK/ERK pathway is the primary target for radicicol's effects.

Main Methods:

  • Treatment of various transformed cells with radicicol.
  • Assessment of cell phenotype changes, including cell spreading and anchorage-independent growth.
  • Measurement of tropomyosin isoform TM-2 expression.
  • Analysis of Raf degradation, ERK phosphorylation, and transcription factor activity (AP-1, SRF).

Main Results:

  • Radicicol induced cell spreading, suppressed anchorage-independent growth, and increased TM-2 expression in MEK-1 and ras-transformed cells.
  • These phenotypic effects occurred at radicicol concentrations lower than those affecting Raf levels or ERK phosphorylation.
  • Low radicicol concentrations significantly inhibited activator protein (AP-1) and serum response factor (SRF)-mediated transcription.

Conclusions:

  • Radicicol's reversion of the transformed phenotype is not primarily mediated by Raf depletion or disruption of proximal Ras/Raf/MEK/ERK signaling.
  • Inhibition of transcriptional activities regulated by AP-1 and SRF at low concentrations suggests upstream signaling interference as a key mechanism.

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