Hunterian Lecture. Regulation of hypoxia-inducible factor 1 (HIF-1) by nitric oxide in oral squamous cell carcinoma.
BACKGROUND
Hypoxia is a common feature of many cancers, contributing to tumour progression as well as potentially compromising radiotherapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is an essential component in changing the transcriptional response of tumours under hypoxia and it targets the transcription of many genes involved in cancer biology. Over-expression of HIF-1 has been associated with increased patient mortality in several cancer types. Regulation of HIF-1 by the signalling molecule nitric oxide (NO) is becoming increasingly recognised.


METHODS
Three oral cancer cell lines were used to investigate the effects of NO synthase enzymes (NOS) on HIF-1alpha expression under both normal oxygen and hypoxic conditions. The effect of NOS inhibition was evaluated with the drug L-NMMA. Protein expression was determined with Western blotting.


CONCLUSIONS
HIF-1alpha expression occurred following exposure of cells to 3% oxygen for 8 h in all three cell lines, and its expression was found to be dependent on NOS activity, being reduced or inhibited by L-NMMA. Although the mechanism remains to be established, NO appears to play a role in the expression of HIF-1alpha in oral cancer. The possible clinical implications of targeting HIF-1 in cancer are discussed.
Brennan
P A
PA
Department of Head and Neck Surgery, Queen Alexandra Hospital, Portsmouth, UK. peter.brennan@porthosp.nhs.uk
Quintero
M
M
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009062:Mouth Neoplasms / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase