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

Abstract

Abstract. Regular aspirin intake is associated with a reduction in the incidence of colorectal cancer. Aspirin has been shown to be cytotoxic to colorectal cancer cells in vitro. The molecular basis for this cytotoxicity is controversial, with a number of competing hypotheses in circulation. One suggestion is that the protective effect is related to the induction of expression of the DNA mismatch repair (MMR) proteins hMLH1, hMSH2, hMSH6 and hPMS2 in DNA MMR proficient cells. We report that treatment of the DNA MMR competent/p53 mutant colorectal cancer cell line SW480 with 1 mM aspirin for 48 h caused changes in mRNA expression of several key genes involved in DNA damage signalling pathways, including a significant down-regulation in transcription of the genes ATR, BRCA1 and MAPK12. Increases in the transcription of XRCC3 and GADD45· genes are also reported. Regulation of these genes could potentially have profound effects on colorectal cancer cells and may play a role in the observed chemoprotective effect of aspirin in vivo. Although a correlation was not seen between transcript and protein levels of ATR, BRCA1 and GADD45·, an increase in XRCC3 encoded protein expression upon aspirin treatment in SW480 cells was observed by immunoblotting, immunofluorescence and immunohistochemical analysis. This is the first report of XRCC3 gene transcription and encoded protein expression being susceptible to exposure to the non-steroidal anti-inflammatory drug, aspirin. Furthermore, this study indicates that alterations in gene transcription seen in microarray studies must be verified at the protein level.

The Synergistic Effect of APE1/Ref-1 and Aspirin Enhances PEO14 Ovarian Cancer Cell Apoptosis via Parp Cleavage

“…Accumulating evidence suggests that the abnormal acetylation of DNA repair proteins contributes to the impairment of DNA repair mechanisms, the development and progression of cancer, and the sensitivity of cancer cells to chemotherapy. These insights into the role of acetylation and its implications in cancer have been reported previously [20,28]. In the present study, we treated PEO14 cells with 3 mM aspirin for 24 h to induce hyperacetylation, which did not result in cytotoxic effects.…”

Aspirin and Cancer Survival: An Analysis of Molecular Mechanisms

“…The first group includes primary genes controlled directly by aspirin, i.e., PTGS2 and PTGES2 . The second group consists of genes involved in cell signaling and cell proliferation like cMyc , EGFR , BCL2 , WNT , KRAS , WNT6 , BRAF , MUC1 , PIK3CA , PARP1 , PARP2 , STAT3 , MAPK , JAK/STAT , and BAX [ 6 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]; the third group includes genes for cytokines or their receptors (e.g., IFNγ , IL1β , IL2 , IL4 , IL5 , IL6 , IL7 , IL8 , IL10 , IL12 (p70) , IL13 , IL17 , CXCR1 , CXCR2 , PTGS2 , PTGES2 , NFKB1 , and TNFα ) [ 30 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]; and the fourth group consists of tumor suppressor genes including P53 , BRCA1 [ 43 ], hMLH1 , hMSH2 , hMSH6 , and hPMS2 [ 44 , 45 ] ( Table 1 ).…”

“…Several previous studies have shown that aspirin can affect DNA repair of genes. For example, treatment of a DNA MMR competent/p53 mutant colorectal cancer cell line with aspirin for 48 h led to DNA damage pathway gene expression, including BRCA1 [ 45 ]. A later study found that feeding aspirin to Dalton cell lymphoma-bearing mice resulted in cell cycle arrest in the G0/G1 phase [ 34 ].…”

Aspirin impairs acetyl-coenzyme A metabolism in redox-compromised yeast cells

“…Induced alterations in the expression profile of gene transcripts do not necessarily correlate with expression of their respective encoded proteins 45 . Moreover, post-translational modifications of encoded gene products are not taken into account by microarrays and qRT-PCR techniques.…”