Radiosensitization by targeting radioresistance-related genes with protein kinase A inhibitor in radioresistant cancer cells.
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.
Chin
Chur
C
Department of Biochemistry, Pusan National University Hospital, Busan 602-739, Korea.
Bae
Jae Ho
JH
Kim
Mi Ju
MJ
Hwang
Jee Young
JY
Kim
Su Jin
SJ
Yoon
Man Soo
MS
Lee
Min Ki
MK
Kim
Dong Wan
DW
Chung
Byung Seon
BS
Kang
Chi Dug
CD
Kim
Sun Hee
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*
D009363:Neoplasm Proteins; D017868:Cyclic AMP-Dependent Protein Kinases