Mismatch repair protein deficiency compromises cisplatin-induced apoptotic signaling.
Mismatch repair (MMR) proteins participate in cytotoxicity induced by certain DNA damage-inducing agents, including cisplatin (cis-diamminedichloroplatinum(II), CDDP), a cancer chemotherapeutic drug utilized clinically to treat a variety of malignancies. MMR proteins have been demonstrated to bind to CDDP-DNA adducts and initiate MMR protein-dependent cell death in cells treated with CDDP; however, the molecular events underlying this death remain unclear. As MMR proteins have been suggested to be important in clinical responses to CDDP, a clear understanding of MMR protein-dependent, CDDP-induced cell death is critical. In this report, we demonstrate MMR protein-dependent relocalization of cytochrome c to the cytoplasm and cleavage of caspase-9, caspase-3, and poly(ADP-ribose) polymerase upon treatment of cells with CDDP. Chemical inhibition of caspases specifically attenuates CDDP/MMR protein-dependent cytotoxicity, suggesting that a caspase-dependent signaling mechanism is required for the execution of this cell death. p53 protein levels were up-regulated independently of MMR protein status, suggesting that p53 is not a mediator of MMR-dependent, CDDP-induced death. This work is the first indication of a required signaling mechanism in CDDP-induced, MMR protein-dependent cytotoxicity, which can be uncoupled from other CDDP response pathways, and defines a critical contribution of MMR proteins to the control of cell death.
Topping
Ryan P
RP
Departments of Cancer Biology and Biochemistry and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Wilkinson
John C
JC
Scarpinato
Karin Drotschmann
KD
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051718:MutS Homolog 2 Protein / Q000172:deficiency* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011480:Protease Inhibitors; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D002945:Cisplatin