Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab

Invest New Drugs. 2013 Jun;31(3):516-24. doi: 10.1007/s10637-012-9875-x. Epub 2012 Sep 6.

Abstract

The epidermal growth factor receptor (EGFR) is a member of the HER family receptors and its activation induced by its natural ligand EGF results in colon cancer growth and progression. Panitumumab (pmAb) is a fully human IgG2 anti-EGFR antibody that blocks the EGFR actions. In the present study, we evaluated the effects of pmAb on the EGF-mediated cellular responses in a panel of colon cancer cells (HCT-8, HT-29, DLD-1 and HCT-116). HCT-1116 and DLD-1 cells showed no significant EGF-dependent cell proliferation; HT-29 and HCT-8 exhibited an EGF-dependent proliferation, with HCT-8 cells to be the most responsive with significant EGFR phosphorylation upon treatment with EGF. The effects of pmAb were then evaluated in the most EGF-responsive cells, HCT-8. In that respect, pmAb impedes the signaling cascade mediated by EGFR intracellular phosphorylation and activity of focal adhesion kinase (FAK) as well as the EGF-induced invasive and migratory potential of colon cancer cells. At the level of matrix effectors implicated in colon cancer progression we report that pmAb is a potent inhibitor of constitute and EGF-mediated gene expression of certain matrix effectors, such as membrane-type 1 metalloproteinase (MT1-MMP), extracellular metalloproteinases inducer (EMMPRIN), urokinase plasminogen activator (uPA) and syndecan-4. The obtained data demonstrated that pmAb is a specific blocker of EGF-mediated EGFR activation, resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth, migration and invasiveness as well as of matrix effector implicated in cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Basigin / genetics
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / metabolism*
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Gene Expression / drug effects
  • Humans
  • Matrix Metalloproteinase 14 / genetics
  • Panitumumab
  • Syndecan-4 / genetics
  • Urokinase-Type Plasminogen Activator / genetics
  • Wound Healing / drug effects

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • BSG protein, human
  • SDC4 protein, human
  • Syndecan-4
  • Basigin
  • Epidermal Growth Factor
  • Panitumumab
  • ErbB Receptors
  • Focal Adhesion Protein-Tyrosine Kinases
  • Urokinase-Type Plasminogen Activator
  • MMP14 protein, human
  • Matrix Metalloproteinase 14