Involvement of DNA-dependent protein kinase in regulation of the mitochondrial heat shock proteins.
Since DNA-dependent protein kinase (DNA-PK) has been known to play a protective role against drug-induced apoptosis, the role of DNA-PK in the regulation of mitochondrial heat shock proteins by anticancer drugs was examined. The levels of basal and drug-induced mitochondrial heat shock proteins of drug-sensitive parental cells were higher than those of multidrug-resistant (MDR) cells. We also demonstrated that the development of MDR might be correlated with the increased expression of Ku-subunit of DNA-PK and concurrent down-regulation of mitochondrial heat shock proteins. The basal mtHsp70 and Hsp60 levels of Ku70(-/-) cells, which were known to be sensitive to anticancer drugs, were higher than those of parental MEF cells, but conversely these mitochondrial heat shock proteins of R7080-6 cells over-expressing both Ku70 and Ku80 were lower than those of parental Rat-1 cells. Also, the mtHsp70 and Hsp60 levels of DNA-PKcs-deficient SCID cells were higher than those of parental CB-17 cells. Our results suggest the possibility that mitochondrial heat shock protein may be one of determinants of drug sensitivity and could be regulated by DNA-PK activity.
Um
Jee Hyun
JH
Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
Kang
Chi Dug
CD
Hwang
Byung Wook
BW
Ha
Mee Young
MY
Hur
Joong Gu
JG
Kim
Dong Wan
DW
Chung
Byung Seon
BS
Kim
Sun Hee
SH
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D018834:Chaperonin 60 / Q000378:metabolism*; D004265:DNA Helicases; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats
D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D018834:Chaperonin 60; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen