title: Chemotherapy-induced activation of ADAM-17: a novel mechanism of drug resistance in colorectal cancer.
abstract: OBJECTIVE
  We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.
  
  
  METHODS
  In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.
  
  
  RESULTS
  Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-alpha, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA-mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.
  
  
  CONCLUSIONS
  Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC.
authors.affiliation: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Joan N
authors.initials: JN
authors.lastname: Kyula
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Schaeybroeck
authors.forename: Joanne
authors.initials: J
authors.lastname: Doherty
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Fenning
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D005472:Fluorouracil