Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known cancer preventives, which have been largely attributed to their antiproliferative and apoptosis-inducing activities. In this study, we show that microsatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and hMSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)]. This effect was reversible, time and concentration dependent, and appeared independent of proliferation rate and cyclooxygenase function. In contrast, the MSI phenotype of a hPMS2-deficient endometrial cancer cell line was unaffected by aspirin/sulindac. We show that the MSI reduction in the susceptible MMR-deficient cells was confined to nonapoptotic cells, whereas apoptotic cells remained unstable and were eliminated from the growing population. These results suggest that aspirin/sulindac induces a genetic selection for microsatellite stability in a subset of MMR-deficient cells and may provide an effective prophylactic therapy for hereditary nonpolyposis colorectal cancer kindreds where alteration of the hMSH2 and hMLH1 genes are associated with the majority of cancer susceptibility cases.
Rüschoff
J
J
Institute of Pathology, University of Regensburg, D-93042 Regensburg, Germany. josef.rueschoff@klinik.uni-regensburg.de
Wallinger
S
S
Dietmaier
W
W
Bocker
T
T
Brockhoff
G
G
Hofstädter
F
F
Fishel
R
R
D048868:Adaptor Proteins, Signal Transducing; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D001241:Aspirin / Q000494:pharmacology*; D002352:Carrier Proteins; D018890:Chemoprevention; D002999:Clone Cells / Q000378:metabolism; D003001:Cloning, Molecular; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000628:therapy*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D013467:Sulindac; D013997:Time Factors; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C501486:MLH1 protein, human; C098790:MSH6 protein, S cerevisiae; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D013467:Sulindac; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D001241:Aspirin