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The hypoxia-inducible factor-1α is a negative factor for tumor therapy

Oncogene volume 22, pages 3213–3220 (2003)Cite this article

Abstract

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-1α are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1α-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-1α-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-1α genotype. Functional repair of a fragmented reporter gene was decreased in HIF-1α-deficient cells. Thus, hypoxia-independent basal HIF-1α 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.

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Abbreviations

DFX:

deferoxamine mesylate

HIF-1:

hypoxia-inducible factor-1

IC50:

50% inhibitory concentration

MEF:

mouse embryonic fibroblast

pVHL:

von Hippel–Lindau tumor suppressor protein

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Acknowledgements

We thank B Stier and S Schindler for excellent technical assistance, I Desbaillets for helpful advice and W Jelkmann for support. This work was supported by grants of the FSP-Oncology, University of Lübeck (to DMK and RHW) and the Deutsche Forschungsgemeinschaft (We2672/1-1 to RHW).

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Author notes

  1. Dörthe M Katschinski

    Present address: Cell Physiology Group, Medical Faculty, Martin-Luther-University Halle, D-06112, Halle, Germany

  2. Annika Unruh, Anke Ressel, Dörthe M Katschinski and Roland H Wenger: The contribution of AU and AR as first authors and DMK and RHW as senior authors was equal

Authors and Affiliations

  1. Institute of Physiology, University of Lübeck, Lübeck, D-23538, Germany

    Annika Unruh, Anke Ressel, Hamid G Mohamed & Dörthe M Katschinski

  2. Department of Biology, University of California, San Diego, 92093, CA, USA

    Randall S Johnson

  3. Clinic for Radiotherapy and Nuclear Medicine, University of Lübeck, Lübeck, D-23538, Germany

    Roger Nadrowitz & Eckart Richter

  4. Carl-Ludwig Institute of Physiology, University of Leipzig, Leipzig, D-04103, Germany

    Roland H Wenger

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Correspondence to Roland H Wenger.

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Unruh, A., Ressel, A., Mohamed, H. et al. The hypoxia-inducible factor-1α is a negative factor for tumor therapy. Oncogene 22, 3213–3220 (2003). https://doi.org/10.1038/sj.onc.1206385

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