Figure 8

Proposed hypothesis for the role of the Myc-Aurora-A pathway in response to topoisomerase I inhibition. In normal conditions, the Aurora-A gene is activated and Myc binds to its promoter in association with Max. Upon treatment, sn38 binds to the topoisomerase I and induces the formation of cleavage complexes. This induces a dowregulation of Myc and an increase in the expression of Mad. Myc/Max binding is inhibited and Mad and/or Miz-1 binds to the Aurora-A promoter. Although this remains to be shown, we speculate that these proteins associates with transcriptional inhibitors such as Gfi-1 or Dnmt3a to induce SAHF foci and Aurora-A downregulation. In colorectal tumors overexpressing Myc, the Myc/Max complex remains associated with the Aurora-A promoter due to a high level of expression and to a downregulation of Mad and Miz-1 expression. As a consequence, Aurora is overexpressed, this protein is not inhibited by topoisomerase I inhibitors and this induces drug resistance.