Exp Mol Med.
2005 Dec;37(6):608-618.
Radiosensitization by targeting radioresistance-related genes with protein kinase A inhibitor in radioresistant cancer cells
- Affiliations
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- 1Department of Biochemistry, Pusan National University Hospital, Busan 602-739, Korea. ksh7738@pusan.ac.kr
- 2Department of Biochemistry, Pusan National University Hospital, Busan 602-739, Korea.
- 3Department of Obstetrics and Gynecology, Pusan National University Hospital, Busan 602-739, Korea.
- 4Department of Internal Medicine, Pusan National University Hospital, Busan 602-739, Korea.
- 5Research Center for Ischemic Tissue Regeneration, College of Medicine, Pusan National University, Busan, Korea.
- 6Medical Research Institutes, Pusan National University Hospital, Busan 602-739, Korea.
- 7Cancer Research Center, Pusan National University Hospital, Busan 602-739, Korea.
- 8Department of Microbiology, College of Natural Sciences, Chang Won National University, Chang Won 641-773, Korea.
Abstract
- Here we determined which radiation-responsive genes were altered in radioresistant CEM/IR and FM3A/IR variants, which showed higher resistance to irradiation than parental human leukemia CEM and mouse mammary carcinoma FM3A cells, respectively and studied if radioresistance observed after radiotherapy could be restored by inhibition of protein kinase A. The expressions of DNA-PKcs, Ku70/80, Rad51 and Rad54 genes that related to DNA damage repair, and Bcl-2 and NF-kappaB genes that related to antiapoptosis, were up-regulated, but the expression of proapototic Bax gene was down-regulated in the radioresistant cells as compared to each parental counterpart. We also revealed that the combined treatment of radiation and the inhibitor of protein kinase A (PKA) to these radioresistant cells resulted in synergistic inhibition of DNA-PK, Rad51 and Bcl-2 expressions of the cells, and consequently restored radiosensitivity of the cells. Our results propose that combined treatment with radiotherapy and PKA inhibitor can be a novel therapeutic strategy to radioresistant cancers.
Keyword
MeSH Terms
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Animals
Apoptosis/drug effects
Cell Line, Tumor
Cyclic AMP-Dependent Protein Kinases/*antagonists & inhibitors/metabolism
DNA Damage/drug effects
DNA Repair/drug effects
Gamma Rays
Gene Expression Regulation, Neoplastic/radiation effects
Genes, bcl-2
Humans
Mice
Neoplasm Proteins/genetics/metabolism
Neoplasms/enzymology/*genetics
Radiation Tolerance/*genetics
Research Support, Non-U.S. Gov't
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