The EGFR-STAT3 oncogenic pathway up-regulates the Eme1 endonuclease to reduce DNA damage after topoisomerase I inhibition.
The epidermal growth factor receptor (EGFR)-src-signal transducers and activators of transcription 3 (STAT3) oncogenic pathway plays a central role in tumorigenesis and is involved not only in cell transformation but also in tumor escape to genotoxic treatments. Despite its importance, the molecular mechanisms by which this signaling pathway induces resistance to DNA damage remain most of the time to be characterized. In this study, we show that the EGFR-src pathway is activated in response to topoisomerase I inhibition. After treatment, this signaling cascade induced the activation of STAT3 and the binding of the transcription factor to the promoter of the Eme1 gene. Eme1 is an endonuclease involved in the processing of DNA damage after topoisomerase I inhibition. These results suggest a model by which the STAT3-mediated activation of Eme1 prevents DNA damage and enhances cell survival in response to topoisomerase inhibition. This survival pathway was inhibited by a combined treatment with a src inhibitor, SKI, and with cetuximab, a monoclonal antibody directed against the EGFR that is widely used in the treatment of colorectal cancers. We therefore propose that the benefit of anti-EGFR therapy relies on an increase of DNA damage generated by topoisomerase I inhibition.
Vigneron
Arnaud
A
Cancer Center Paul Papin, Institut National de la Sante et de la Recherche Medicale U892, Université d'Angers, Angers, France.
Gamelin
Erick
E
Coqueret
Olivier
O
D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D004249:DNA Damage; D004706:Endodeoxyribonucleases / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059004:Topoisomerase I Inhibitors; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D066246:ErbB Receptors; D019061:src-Family Kinases; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D002166:Camptothecin