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Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression

Bin Zhang1, George C Prendergast, Robert G Fenton

  • 1Greenebaum Cancer Center, University of Maryland Medical System, Baltimore, Maryland 21201, USA.

Cancer Research
|January 26, 2002
PubMed

Insights

Farnesyltransferase inhibitors (FTIs) up-regulate Fas expression, increasing tumor cell sensitivity to immune attack. FTIs also inhibit vascular endothelial growth factor (VEGF), potentially reducing tumor angiogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Host-tumor interactions are crucial for tumor progression.
  • Oncogenic Ras inhibits Fas expression, conferring resistance to Fas-induced cell death.
  • Ras-transformed cells require modulation of Fas and VEGF for altered host-tumor interactions.

Purpose of the Study:

  • To investigate the effect of farnesyltransferase inhibitor (FTI) LB42722 on Fas expression and Fas-induced apoptosis in Ras-transformed cells.
  • To determine if FTI affects vascular endothelial growth factor (VEGF) expression.
  • To compare FTI effects with those of a histone deacetylase inhibitor.

Main Methods:

  • Culture of Ras-transformed cells with FTI LB42722 under basal and cytokine-stimulated conditions.
  • Analysis of fas mRNA levels, Fas cell surface expression, and Fas-induced apoptosis.
  • Assessment of VEGF expression and effects of histone deacetylase inhibitor (trichostatin A).

Main Results:

  • FTI LB42722 up-regulated Fas expression, increasing fas mRNA, cell surface Fas, and Fas-induced apoptosis.
  • FTI treatment also inhibited vascular endothelial growth factor (VEGF) expression.
  • Histone deacetylase inhibitor (trichostatin A) caused morphological reversion and G(1) arrest but did not induce Fas.

Conclusions:

  • Inhibition of oncogenic Ras by FTI can enhance tumor sensitivity to immune cells via Fas up-regulation.
  • FTI-mediated down-regulation of VEGF may inhibit tumor angiogenesis.
  • FTI offers a dual mechanism to alter host-tumor interactions, impacting both immune surveillance and tumor vascularization.

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