The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy.
Tumor hypoxia negatively regulates cell growth and causes a more malignant phenotype by increasing the expression of genes encoding angiogenic, metabolic and metastatic factors. Of clinical importance, insufficient tumor oxygenation affects the efficiency of chemotherapy and radiotherapy by poorly understood mechanisms. The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes and HIF-1 is constitutively upregulated in several tumor types. HIF-1 might thus be implicated in tumor therapy resistance. We found that transformed mouse embryonic fibroblasts deficient for HIF-1alpha are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1alpha-deficient cells was because of apoptosis and did not involve p53 induction. Tumor chemotherapy of experimental fibrosarcoma in immunocompromised mice with carboplatin and etoposide confirmed the enhanced susceptibility of HIF-1alpha-deficient cells. Agents that did not cause DNA double-strand breaks, such as DNA-synthesis inhibitors or a DNA single-strand break-causing agent equally impaired cell growth, independent of the HIF-1alpha genotype. Functional repair of a fragmented reporter gene was decreased in HIF-1alpha-deficient cells. Thus, hypoxia-independent basal HIF-1alpha expression in tumor cells, as known from untransformed embryonic stem cells, is sufficient to induce target gene expression, probably including DNA double-strand break repair enzymes.
Unruh
Annika
A
Institute of Physiology, University of Lübeck, D-23538 Lübeck, Germany.
Ressel
Anke
A
Mohamed
Hamid G
HG
Johnson
Randall S
RS
Nadrowitz
Roger
R
Richter
Eckart
E
Katschinski
Dörthe M
DM
Wenger
Roland H
RH
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D016190:Carboplatin / Q000627:therapeutic use / Q000633:toxicity; D002461:Cell Line, Transformed; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000633:toxicity; D005047:Etoposide / Q000627:therapeutic use / Q000633:toxicity; D017353:Gene Deletion; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents / Q000633:toxicity; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D016190:Carboplatin