Inflammation, but not hypoxia, mediated HIF-1 alpha 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-alpha, has been observed to be regulated by the COX-2 product PGE2. Here we show that HIF-1 alpha protein significantly accumulated in human breast cancer MDA-MB-231 cells in response to the pro-inflammatory cytokine IL-I beta, but not in COX-2-silenced MDA-MB-231 cells. In contrast HIF-1 alpha expression could be detected in COX-2-silenced cells in response to the hypoxia-mimetic agent CoCl2 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-1 beta-dependent COX-2 and HIF-1 alpha but are independent of hypoxia.