Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection

Abstract

Nonsteroidal anti-inf lammatory drugs (NSAIDs) are well-known cancer preventives, which have been largely attributed to their antiproliferative and apoptosisinducing 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 aspirin͞sulindac. 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 aspirin͞sulindac induces a genetic selection for microsatellite stability in a subset of MMRdeficient 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.

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

“…Chemopreventive agents should be developed that specifically target precancerous cells in which an incipient defect in MMR is propelling them to malignancy. Genetic selection for microsatellite stability in MMR-defective cells by the nonsteroidal anti-inflammatory drugs aspirin and sulindac 120 offers concrete hope that this approach might be effective. At the same time, novel radio-and chemotherapeutic strategies will have to take into account the MMR proficiency or deficiency of the individual tumor.…”

Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line

“…(9)], with a range of theories in circulation such as; cyclooxygenase (COX) inhibition (7,10), NF-κB inhibition (11)(12)(13), NF-κB activation (14,15), down-regulation of Bcl-2 expression (16,17), thus making the cells less resistant to the initiation of apoptosis, and down-regulation of c-Myc, cyclin D1, cyclin A and proliferating cell nuclear antigen (PCNA) (18), the intrinsic antioxidant activity of aspirin preventing double stranded DNA breaks (19), aspirin induces translocation of Bax to mitochondria (20), NSAIDSs up-regulate 15-lipoxygenase-1 expression (21), inhibition of cytosolic phospholipase A 2 expression (22), depletion of intracellular polyamines (23), increased Rac 1 expression (24), increased NSAID-activated gene (NAG-1) protein (25 and refs. therein), selection for microsatellite stability (26), and induction of the DNA mismatch repair (MMR) proteins hMLH1, hMSH2, hMSH6 and hPMS2 in DNA MMR proficient cells, which ultimately facilitates programmed cell death (27). Identifying and understanding pathway modulation by aspirin is possibly key to understanding its chemopreventative effect on colorectal cancer.…”

Aspirin-induced nuclear translocation of NFκB and apoptosis in colorectal cancer is independent of p53 status and DNA mismatch repair proficiency

“…p53 dysfunction and DNA MMR deficiency are almost wholly mutually exclusive (Cottu et al, 1996;Samowitz et al, 2001). p53 signalling and DNA MMR have been identified as potential molecular targets for NSAIDs (Ruschoff et al, 1998;Shao et al, 2000;Goel et al, 2003), suggesting that the anti-tumour effect may, in part, involve countering the effects of genetic instability in CRC. Such genetic aberrations in tumours have also been shown to be involved in determining response to chemotherapeutic agents (O'Connor et al, 1997;Weller, 1998;Ribic et al, 2003).…”