Presence of MLH1 protein aggravates the potential of the HSP90 inhibitor radicicol to sensitize tumor cells to cisplatin.
MLH1 is one of five proteins crucial to DNA mismatch repair (MMR) function the loss of which is associated with a cisplatin resistance phenotype in tumor cells. An experimental approach was designed to determine whether the presence or absence of MLH1 affects the potential of radicicol to increase the sensitivity of tumor cells to cisplatin and oxaliplatin, and whether perhaps radicicol increases sensitivity to cisplatin specifically in cisplatin-resistant, MLH1-deficient cells. Radicicol is a novel specific inhibitor for heat shock protein 90 (HSP90) and structurally unrelated to geldanamycin. Clonogenic data demonstrated that sublethal concentrations of radicicol increased the sensitivity to cisplatin and to oxaliplatin in both MLH1-proficient cells and MLH1-deficient cells. Notably, the radicicol-imposed increase in sensitivity to cisplatin was up to 1.6-fold higher in MLH1-proficient cells than in MLH1-deficient cells, whereas no difference in the extent of the increase in sensitivity between the two sublines was observed for oxaliplatin. This indicates that the presence of MLH1 protein aggravates the radicicol-imposed increase in sensitivity of cells to cisplatin but not to oxaliplatin. However, the increases in platinum drug sensitivity imposed by radicicol observed in the clonogenic assay were not accompanied by reproducible alterations in the susceptibility to apoptosis and to changes in cell cycling. Although not conclusive at this point, the results seem to argue against radicicol as a means to selectively re-sensitize cisplatin-resistant, MLH1-deficient tumor cells to this drug. But they may point to a possible functional relationship between HSP90 and MLH1, where HSP90 might affect the function of MLH1 in a way that this leads to the counter-regulation of cytotoxic pathways initiated by MMR as a consequence of the presence of DNA damage introduced by cisplatin.
Fedier
Andre
A
Department of Gynecology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. andre.fedier@usz.ch
Stuedli
Angela
A
Fink
Daniel
D
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005838:Genotype; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; C501486:MLH1 protein, human; D018942:Macrolides; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000070957:MutL Protein Homolog 1; C035359:monorden; D002945:Cisplatin