Inflammation, but not hypoxia, mediated HIF-1alpha activation depends on COX-2.
The COX pathway has been a target for pharmaceutical intervention in diseases with a high inflammatory component ranging from asthma and Alzheimer's to arthritis and cancer. A major transcriptional promoter of the malignant phenotype, HIF-1alpha, has been observed to be regulated by the COX-2 product PGE2. Here we show that HIF-1alpha protein significantly accumulated in human breast cancer MDA-MB-231 cells in response to the pro-inflammatory cytokine IL-1beta, but not in COX-2-silenced MDA-MB-231 cells. In contrast HIF-1alpha expression could be detected in COX-2- silenced cells in response to the hypoxia-mimetic agent CoCl(2) and hypoxia. Gene expression profiling in COX-2-containing and COX-2-silenced cells showed that the hypoxia-induced transcriptional response is largely unaffected by COX-2 silencing. These data suggest that the profound effects of COX-2 silencing on inhibiting invasion, tumor growth and metastasis from MDA-MB-231 cells are dependent on the induction of IL-1beta-dependent COX-2 and HIF-1alpha but are independent of hypoxia
Stasinopoulos
Ioannis
I
The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
O'Brien
David R
DR
Bhujwalla
Zaver M
ZM
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D020868:Gene Silencing; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
C497396:ARNT protein, human; D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051546:Cyclooxygenase 2; D008249:Protein-Lysine 6-Oxidase