TNFalpha induces HIF-1alpha expression through activation of IKKbeta.
The transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) is regulated by oxygen availability as well as various inflammatory mediators, including tumor necrosis factor alpha (TNFalpha). Early work suggested that the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are involved in TNFalpha-mediated HIF-1alpha accumulation and activation under normoxic conditions. Here, we provide evidence showing that IkappaB kinase beta (IKKbeta) is required for HIF-1alpha regulation by TNFalpha. We found that TNFalpha enhances HIF-1alpha protein expression in various breast cancer cell lines under either normoxic or hypoxia-mimicking conditions, but has little effect on the HIF-1alpha mRNA level. Increased HIF-1alpha expression was found in IKKbeta stable clones and transient transfectants, and depletion of IKKbeta consistently reduced the amount of HIF-1alpha protein. Treatment of cells with the IKKbeta inhibitor Bay 11-7082 reduced the TNFalpha-induced HIF-1alpha expression, suggesting that IKKbeta is required in this signaling pathway. Decreased expression of vascular endothelial growth factor (VEGF), a direct target of HIF-1alpha, was shown in IKKbeta-knockout mouse embryonic fibroblast cells. We further demonstrated a positive correlation between IKKbeta and VEGF expression in primary human breast cancer specimens. Our findings indicate that TNFalpha-induced HIF-1alpha accumulation is IKKbeta dependent, and may enable further understanding of the HIF-1alpha regulation by inflammatory signals.
Kuo
Hsu-Ping
HP
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lee
Dung-Fang
DF
Xia
Weiya
W
Wei
Yongkun
Y
Hung
Mien-Chie
MC
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051550:I-kappa B Kinase