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Pharmacogenomic profiling and pathway analyses identify MAPK-dependent migration as an acute response to SN38 in p53 null and p53-mutant colorectal cancer cells. | LitMetric

AI Article Synopsis

  • * Research revealed that the absence of p53 significantly alters gene expression and activates certain pathways related to cell movement in colorectal cancer cells after treatment with irinotecan's active form, SN38.
  • * Treatment with SN38 enhances the migratory ability of p53-null and p53-mutant cancer cells, suggesting a potential for metastasis, which can be reduced by inhibiting the MAPK pathway.

Article Abstract

The topoisomerase I inhibitor irinotecan is used to treat advanced colorectal cancer and has been shown to have p53-independent anticancer activity. The aim of this study was to identify the p53-independent signaling mechanisms activated by irinotecan. Transcriptional profiling of isogenic HCT116 p53 wild-type and p53 null cells was carried out following treatment with the active metabolite of irinotecan, SN38. Unsupervised analysis methods showed that p53 status had a highly significant impact on gene expression changes in response to SN38. Pathway analysis indicated that pathways involved in cell motility [adherens junction, focal adhesion, mitogen-activated protein kinase (MAPK), and regulation of the actin cytoskeleton] were significantly activated in p53 null cells, but not p53 wild-type cells, following SN38 treatment. In functional assays, SN38 treatment increased the migratory potential of p53 null and p53-mutant colorectal cancer cell lines, but not p53 wild-type lines. Moreover, p53 null SN38-resistant cells were found to migrate at a faster rate than parental drug-sensitive p53 null cells, whereas p53 wild-type SN38-resistant cells failed to migrate. Notably, cotreatment with inhibitors of the MAPK pathway inhibited the increased migration observed following SN38 treatment in p53 null and p53-mutant cells. Thus, in the absence of wild-type p53, SN38 promotes migration of colorectal cancer cells, and inhibiting MAPK blocks this potentially prometastatic adaptive response to this anticancer drug.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428848PMC
http://dx.doi.org/10.1158/1535-7163.MCT-12-0207DOI Listing

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