Anti-EGFR and ErbB-2 antibodies attenuate cyclooxygenase-2 expression and cooperatively inhibit survival of human colon cancer cells

Cancer Lett. 2007 Jun 28;251(2):237-46. doi: 10.1016/j.canlet.2006.11.020. Epub 2006 Dec 26.

Abstract

Cyclooxygenase-2 (COX-2) is a transcriptional target and downstream effector of the ErbB-1 (EGFR) and ErbB-2 signaling pathways. We found that anti-EGFR and anti-ErbB-2 antibodies inhibited ERK phosphorylation and downregulated COX-2 protein expression in HCA-7 human colon carcinoma cells. Both antibodies also augmented the cytotoxic effects of the selective COX-2 inhibitor, NS-398. Inhibition of EGFR and ErbB-2 attenuated cell growth by increasing cell death, and the antibody combination suppressed cell growth to a greater extent than did either antibody alone. In conclusion, EGFR and ErbB-2 regulate ERK-mediated COX-2 expression and their selective inhibition enhanced NS-398-induced cell death. Cooperative inhibition of cell growth by EGFR and ErbB-2 blockade suggests the therapeutic potential of targeting multiple ErbB receptors.

MeSH terms

  • Antibodies / pharmacology
  • Cell Line, Tumor
  • Cell Survival
  • Colonic Neoplasms / metabolism*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase Inhibitors
  • ErbB Receptors / immunology
  • ErbB Receptors / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Nitrobenzenes / pharmacology
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / physiology*
  • Sulfonamides / pharmacology

Substances

  • Antibodies
  • Cyclooxygenase Inhibitors
  • Nitrobenzenes
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Extracellular Signal-Regulated MAP Kinases