Sep 30, 2009

Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity

Gastroenterology
Jing XueJing Fang

Abstract

Prolyl hydroxylase (PHD) hydroxylates hypoxia inducible factor (HIF) alpha, leading to HIFalpha degradation. The PHD family comprises PHD1, PHD2, and PHD3. The enzymatic activity of PHDs is O(2)-dependent, so PHDs are believed to be oxygen sensors as well as tumor suppressors. However, the expression pattern of PHDs in colorectal cancer and the correlation between their expression level and tumorigenesis is unclear. We determined the expression of PHDs in 60 human primary colorectal carcinoma tissues, paired with normal colorectal tissues. PHD3 expression levels were knocked down using small interfering RNA (siRNA); cells were analyzed by immunoblotting, immunoprecipitation, and histochemical analyses. In vivo tumor growth was analyzed in nu/nu mice. Expression of PHD3 is decreased in colorectal cancer tissues. Decreased expression of PHD3 is associated with higher tumor grade and metastasis. PHD3 inhibits phosphorylation of inhibitor of kappaB (IkappaB) kinase (IKK) beta and activation of (NF) kappaB, independent of its hydroxylase activity. PHD3 associates with IKKbeta but does not target it for destruction; instead, PHD3 blocks the interaction between IKKbeta and Hsp90 that is required for phosphorylation of IKKbeta. Knockdo...Continue Reading

Mentioned in this Paper

Real-Time Polymerase Chain Reaction
Positive Regulation of NF-kappaB Transcription Factor Activity
Tumor Suppressor Genes
Transfection
Tumor Necrosis Factor-alpha
RNA, Small Interfering
GAPDH gene
Receptor Down-Regulation
Protein Phosphorylation
HSP90AA1 gene

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