Association of DNA-dependent Protein Kinase With Hypoxia Inducible factor-1 and Its Implication in Resistance to Anticancer Drugs in Hypoxic Tumor Cells

Exp Mol Med. 2004 Jun 30;36(3):233-42. doi: 10.1038/emm.2004.32.

Abstract

Tumor hypoxia contributes to the progression of a malignant phenotype and resistance to ionizing radiation and anticancer drug therapy. Many of these effects in hypoxic tumor cells are mediated by expression of specific set of genes whose relation to therapy resistance is poorly understood. In this study, we revealed that DNA-dependent protein kinase (DNA-PK), which plays a crucial role in DNA double strand break repair, would be involved in regulation of hypoxia inducible factor-1 (HIF-1). HIF-1beta-deficient cells showed constitutively reduced expression and DNA-binding activity of Ku, the regulatory subunit of DNA-PK. Under hypoxic condition, the expression and activity of DNA- PK were markedly induced with a concurrent increase in HIF-1alpha expression. Our result also demonstrated that DNA-PK could directly interact with HIF-1, and especially DNA-PKcs, the catalytic subunit of DNA-PK, could be involved in phosphorylation of HIF-1alpha, suggesting the possibility that the enhanced expression of DNA- PK under hypoxic condition might attribute to modulate HIF-1alpha stabilization. Thus, the correlated regulation of DNA-PK with HIF-1 could contribute to therapy resistance in hypoxic tumor cells, and it provides new evidence for developing therapeutic strategies enhancing the efficacy of cancer therapy in hypoxic tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / immunology
  • Cell Hypoxia
  • Cell Line, Tumor
  • DNA Helicases / immunology
  • DNA Helicases / metabolism
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology*
  • Deferoxamine / pharmacology
  • Drug Resistance, Neoplasm / physiology*
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoprecipitation
  • Ku Autoantigen
  • Neoplasms / enzymology
  • Neoplasms / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Up-Regulation

Substances

  • Antibodies
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • DNA Helicases
  • XRCC5 protein, human
  • Ku Autoantigen
  • Deferoxamine