Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma.
Oxygen deprivation is an important biological feature of tumor growth. We previously showed that in glioma, anoxia increases expression of IL-8, a chemokine and angiogenic factor. Here, we analysed for the first time the biochemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are induced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), only the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the induction is due to the anoxic stress per se. Furthermore, in LN-229 and LN-Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift assays show increased protein binding to the AP-1 site on the IL-8 promoter following anoxia treatment. Finally, in situ hybridization on glioblastoma sections shows that the in vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essential to appropriately target them for antitumoral therapy.
Desbaillets
I
I
Neurosurgery Department, University Hospital (CHUV), Lausanne, Switzerland.
Diserens
A C
AC
de Tribolet
N
N
Hamou
M F
MF
Van Meir
E G
EG
D000818:Animals; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics; D005786:Gene Expression Regulation; D005909:Glioblastoma; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000502:physiology*; D012333:RNA, Messenger; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003609:Dactinomycin; D003035:Cobalt; D004004:Dichlororibofuranosylbenzimidazole; D010100:Oxygen