Ha-rasVal12 Oncogene Increases Susceptibility of NIH/3T3 Cells to Lovastatin

Biochem Biophys Res Commun. 1998 Jul 9;248(1):62-8. doi: 10.1006/bbrc.1998.8911.

Abstract

This study demonstrates that Ha-rasVal12 oncogene overexpression sensitizes NIH/3T3 fibroblasts to lovastatin (LOV) cytotoxicity. This sensitization is through apoptosis, which was characterized by increasing CPP32 (caspase-3) activity and DNA fragmentation. Bcl-2 overexpression increased the resistance of the Ha-ras transformants to LOV and rescued the cells from apoptosis, further confirming that the LOV-sensitive cells died of apoptosis. Further analysis showed that Ha-ras activity inversely correlated with WAF1 activity. LOV treatment suppressed Ha-ras activity but induced WAF1 activity and disrupted the cell population in G0/G1 and S phases. The Ha-ras transformants expressing either dominant negative RasAsn17 or Raf-1CB4 showed reverted susceptibility to LOV. These data confirm the involvement of Ras and demonstrate that Raf-1 signalling is required for LOV-induced cell death. Taken together, the possible action of LOV-induced apoptosis is through suppressing Ha-ras activity and increasing WAF1 activity, which alters cell cycle progression and finally activates suppressed apoptotic pathway in a Fas/Fas-L- and p53-independent fashion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis*
  • Caspase 3
  • Caspases*
  • Cell Line, Transformed
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Cysteine Endopeptidases / metabolism
  • DNA Fragmentation
  • Gene Expression
  • Genes, bcl-2
  • Genes, ras*
  • Interphase
  • Isopropyl Thiogalactoside / pharmacology
  • Lovastatin / pharmacology*
  • Mice
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • S Phase
  • Transfection
  • ras Proteins / metabolism

Substances

  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • NF-kappa B
  • Isopropyl Thiogalactoside
  • Lovastatin
  • Proto-Oncogene Proteins c-raf
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases
  • ras Proteins