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Hypoxia is a key factor in tumor development, contributing to angiogenesis and radiotherapy resistance. Hypoxia-inducible factor-1 (HIF-1) is a major transcription factor regulating the response of cancer cells to hypoxia. However, tumors also contain areas of more severe oxygen depletion, or anoxia. Mechanisms for survival under anoxia are HIF-1alpha independent in Caenorhabditis elegans and, thus, differ from the hypoxic response. Here we report a differential response of cancer cells to hypoxia and anoxia by demonstrating the induction of activating transcription factor-4 (ATF-4) and growth arrest DNA damage 153 (GADD153) protein specifically in anoxia and the lack of induction in hypoxia. By applying RNAi, ATF-4 induction in anoxia was shown to be independent of HIF-1alpha, and desferrioxamine mesylate (DFO) and cobalt chloride induced HIF-1alpha but not ATF-4 or GADD153. Furthermore, the inductive response of ATF-4 and GADD153 was not related to alterations in or arrest of mitochondrial respiration and was independent of von Hippel-Lindau (VHL) disease mutations. In reoxygenated anoxic cells, ATF-4 had a half-life of less than 5 minutes; adding the proteasome inhibitor to normoxic cells up-regulated ATF-4 protein. Extracts from primary human tumors demonstrated more ATF-4 expression in tumors near necrotic areas. Thus, this study demonstrates a novel HIF-1alpha-independent anoxic mechanism that regulates ATF-4 induction at the protein stability level in tumor cells.

Original publication

DOI

10.1182/blood-2003-06-1859

Type

Journal article

Journal

Blood

Publication Date

01/03/2004

Volume

103

Pages

1876 - 1882

Keywords

Activating Transcription Factor 4, CCAAT-Enhancer-Binding Proteins, Cell Line, Tumor, Cobalt, Cysteine Endopeptidases, DNA-Binding Proteins, Deferoxamine, Electron Transport, Glucose, Humans, Hypoxia, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Iron Chelating Agents, Mitochondria, Multienzyme Complexes, Mutation, Nuclear Proteins, Oxygen, Plasmids, Potassium Cyanide, Proteasome Endopeptidase Complex, RNA Interference, RNA, Messenger, Ribonucleases, Time Factors, Transcription Factor CHOP, Transcription Factors, Transfection, Tunicamycin