Loss of DNA mismatch repair in acquired resistance to cisplatin.
Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutations in genes involved in DNA mismatch repair and thereby to resistance to DNA-alkylating agents. Parental cells of the human ovarian adenocarcinoma cell line 2008 expressed hMLH1 when analyzed with immunoblot. One subline selected for resistance to cisplatin (2008/A) expressed no hMLH1, whereas another (2008/C13*5.25) expressed parental levels. Microsatellite instability was readily demonstrated in 2008/A cells but not in 2008 and in 2008/C13*5.25 cells. In addition, the 2008/A cells were 2-fold resistant to methyl-nitro-nitrosoguanidine and had a 65-fold elevated mutation rate at the HPRT locus as compared to 2008 cells, both of which are consistent with the loss of DNA mismatch repair in these cells. To determine whether the loss of DNA mismatch repair itself contributes to cisplatin resistance, studies were carried out in isogenic pairs of cell lines proficient or defective in this function. HCT116, a human colon cancer cell line deficient in hMLH1 function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLH1. Similarly, the human endometrial cancer cell line HEC59, which expresses no hMSH2, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 2 that expresses hMSH2. Therefore, the selection of cells for resistance to cisplatin can result in the loss of DNA mismatch repair, and loss of DNA mismatch repair in turn contributes to resistance to cisplatin.
Aebi
S
S
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla 92093-0812, USA.
Kurdi-Haidar
B
B
Gordon
R
R
Cenni
B
B
Zheng
H
H
Fink
D
D
Christen
R D
RD
Boland
C R
CR
Koi
M
M
Fishel
R
R
Howell
S B
SB
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics*; D001483:Base Sequence; D002273:Carcinogens; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D015151:Immunoblotting; D008769:Methylnitronitrosoguanidine; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D008769:Methylnitronitrosoguanidine; D007041:Hypoxanthine Phosphoribosyltransferase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin