Association of DNA-dependent protein kinase with hypoxia induciblefactor-1 and its implication inresistance to anticancer drugs in hypoxic tum or cells.
- Author:
Jee Hyun UM
1
;
Chi Dug KANG
;
Jae Ho BAE
;
Gin Gu SHIN
;
Do Won KIM
;
Dong Wan KIM
;
Byung Seon CHUNG
;
Sun Hee KIM
Author Information
1. Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, Korea. ksh7738@pusan.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
DNA-PK;
drug resistance;
HIF-1;
hypoxia Introduction
- MeSH:
Antibodies/immunology;
Cell Hypoxia;
Cell Line, Tumor;
DNA Helicases/immunology/metabolism;
DNA-Binding Proteins/genetics/*metabolism/*physiology;
Deferoxamine/pharmacology;
Drug Resistance, Neoplasm/*physiology;
Humans;
Immunoprecipitation;
Neoplasms/enzymology/*metabolism;
Nuclear Proteins/genetics/*metabolism/physiology;
Phosphorylation;
Protein-Serine-Threonine Kinases/metabolism/*physiology;
Research Support, Non-U.S. Gov't;
Transcription Factors/genetics/*metabolism/physiology;
Up-Regulation
- From:Experimental & Molecular Medicine
2004;36(3):233-242
- CountryRepublic of Korea
- Language:English
-
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- 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.
