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RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors

A x Liu1, W Du, J P Liu

  • 1The Wistar Institute, Philadelphia, Glenolden, Pennsylvania, USA.

Molecular and Cellular Biology
|July 27, 2000
PubMed

Insights

Farnesyltransferase inhibitors (FTIs) promote geranylgeranylated RhoB (RhoB-GG) gain, mediating anti-cancer effects. Genetic deletion of RhoB-GG impairs FTI-induced apoptosis and reduces anti-tumor efficacy, confirming RhoB-GG

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Farnesyltransferase inhibitors (FTIs) are investigated for cancer therapy, but their precise mechanism of selective malignant cell inhibition is unclear.
  • RhoB, an endosomal Rho protein regulating receptor trafficking, is implicated in FTI action.
  • FTI treatment leads to increased geranylgeranylated RhoB (RhoB-GG) due to geranylgeranyltransferase I modification.

Purpose of the Study:

  • To investigate the gain-of-function mechanism of RhoB-GG in FTI-mediated anti-cancer effects.
  • To determine if RhoB-GG plays a necessary role in FTI drug action.
  • To assess the impact of RhoB-GG on FTI-induced cellular events and anti-tumor efficacy.

Main Methods:

  • Utilized murine fibroblasts with homozygous deletion of the rhoB gene (nullizygous, -/-) to examine FTI response.
  • Assessed FTI effects on cotransformation, actin cytoskeleton, phenotype, growth inhibition, and apoptosis in RhoB-deficient cells.
  • Evaluated FTI anti-tumor efficacy in xenograft assays using nullizygous cells.

Main Results:

  • RhoB-deficient cells showed defects in FTI response despite complete H-Ras prenylation inhibition.
  • Actin cytoskeletal and phenotypic disruptions were observed in RhoB-deficient cells, suggesting RhoB-GG's role.
  • RhoB-deficient cells were resistant to FTI-induced apoptosis, compromising anti-tumor efficacy in vivo.
  • RhoB-GG sufficiency for growth inhibition was noted, but not necessity under all conditions.

Conclusions:

  • Genetic evidence confirms RhoB-GG as a crucial mediator of FTI's antineoplastic effects.
  • RhoB-GG is essential for FTI-induced apoptosis and contributes significantly to anti-tumor efficacy.
  • FTI therapy's effectiveness is closely linked to the induction of RhoB-GG.

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