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

摘要

The topoisomerase I inhibitor irinotecan is used to treat advanced colorectal cancer and has been shown to have p53-independent anti-cancer activity. The aim of this study was to identify the p53-independent signalling 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 demonstrated 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, 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 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, co-treatment with inhibitors of the MAPK pathway inhibited the increased migration observed following SN38 treatment in p53 null and mutant cells. Thus, in the absence of wild-type p53, SN38 promotes migration of colorectal cancer cells, and inhibiting MAPK blocks this potentially pro-metastatic adaptive response to this anti-cancer drug.