Mismatch Repair Protein Deficiency Compromises Cisplatin-induced Apoptotic Signaling

• Published in: The Journal of biological chemistry 2009-05, Vol.284 (21), p.14029-14039
• Main Authors: Topping, Ryan P., Wilkinson, John C., Scarpinato, Karin Drotschmann
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Caspase Inhibitors; Cell Line, Tumor; Cell Survival - drug effects; Cisplatin - pharmacology; Cytochromes c - metabolism; Cytoplasm - drug effects; Cytoplasm - metabolism; DNA Mismatch Repair - drug effects; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - metabolism; Humans; Inhibitory Concentration 50; MutS Homolog 2 Protein - deficiency; MutS Homolog 2 Protein - metabolism; Poly(ADP-ribose) Polymerases - metabolism; Protease Inhibitors - pharmacology; Protein Transport - drug effects; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M809303200

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.