Involvement of DNA-dependent protein kinase in regulation of the mitochondrial heat shock proteins

Leuk Res. 2003 Jun;27(6):509-16. doi: 10.1016/s0145-2126(02)00264-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Nuclear / metabolism*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cells, Cultured / drug effects
  • Chaperonin 60 / metabolism*
  • DNA Helicases*
  • DNA Repair / drug effects
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Drug Resistance, Multiple*
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / metabolism
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Ku Autoantigen
  • Leukemia / enzymology*
  • Leukemia / pathology
  • Mice
  • Mice, SCID
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats

Substances

  • Antigens, Nuclear
  • Antineoplastic Agents
  • Chaperonin 60
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • HSP70 Heat-Shock Proteins
  • Nuclear Proteins
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • DNA Helicases
  • XRCC5 protein, human
  • Xrcc6 protein, human
  • Xrcc6 protein, mouse
  • Xrcc6 protein, rat
  • Ku Autoantigen