Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

Oncogene. 2006 Feb 9;25(6):877-87. doi: 10.1038/sj.onc.1209117.


The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factor-stimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H- or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Base Sequence
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology
  • Cell Proliferation / drug effects
  • Etoposide / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Growth Substances / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • MAP Kinase Kinase Kinases / drug effects
  • MAP Kinase Kinase Kinases / metabolism
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Proto-Oncogene Proteins c-akt / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-kit / drug effects
  • Proto-Oncogene Proteins c-kit / metabolism
  • Signal Transduction
  • Simvastatin / pharmacology*
  • Tumor Cells, Cultured
  • Up-Regulation
  • ras Proteins / drug effects
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Antineoplastic Agents, Phytogenic
  • Growth Substances
  • Etoposide
  • Simvastatin
  • Proto-Oncogene Proteins c-kit
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • ras Proteins