Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer

J Natl Cancer Inst. 2005 Sep 7;97(17):1272-86. doi: 10.1093/jnci/dji251.

Abstract

Background: The farnesyltransferase inhibitor SCH66336, in combination with other receptor tyrosine kinase inhibitors, inhibits the growth of non-small-cell lung cancer (NSCLC) cells. We examined whether SCH66336 inhibits angiogenesis of aerodigestive tract cancer cells.

Methods: Antiangiogenic activities of SCH66336 against NSCLC, head and neck squamous cell carcinoma (HNSCC), and endothelial cells were examined with cell proliferation, capillary tube formation, and chick aorta (under hypoxic, normoxic, insulin-like growth factor I (IGF)-stimulated, and unstimulated conditions); reverse transcription-polymerase chain reaction; and western blot analyses. The specific roles of the ubiquitin-mediated proteasome machinery, mitogen-activated protein kinase (MAPK) and Akt pathways, and heat shock protein 90 (Hsp90) in the SCH66336-mediated degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) were assessed with ubiquitin inhibitors and adenoviral vectors that express constitutively active MAP kinase kinase (MEK)1, constitutively active Akt, or Hsp90.

Results: SCH66336 showed antiangiogenic activities and decreased the expression of vascular endothelial cell growth factor (VEGF) and HIF-1alpha in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1alpha protein, and ubiquitin inhibitors protected the hypoxia- or IGF-stimulated HIF-1alpha protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1alpha and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1alpha expression in IGF-stimulated or hypoxic cells but not in unstimulated cells.

Conclusions: SCH66336 appears to inhibit angiogenic activities of NSCLC and HNSCC cells by decreasing hypoxia- or IGF-stimulated HIF-1alpha expression and to inhibit VEGF production by inhibiting the interaction between HIF-1alpha and Hsp90, resulting in the proteasomal degradation of HIF-1alpha.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Farnesyltranstransferase
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HSP90 Heat-Shock Proteins / metabolism
  • Head and Neck Neoplasms / drug therapy
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Immunoprecipitation
  • Lung Neoplasms / metabolism
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neovascularization, Pathologic / prevention & control*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Piperidines / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Pyridines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / metabolism*
  • Ubiquitin / antagonists & inhibitors
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Angiogenesis Inhibitors
  • Enzyme Inhibitors
  • HIF1A protein, human
  • HSP90 Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Piperidines
  • Proto-Oncogene Proteins
  • Pyridines
  • Transcription Factors
  • Ubiquitin
  • Vascular Endothelial Growth Factor A
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases
  • Proteasome Endopeptidase Complex
  • lonafarnib