title: Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab.
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.
authors.affiliation: Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110, Patras, Greece.
authors.forename: Ch
authors.initials: Ch
authors.lastname: Gialeli
authors.forename: A D
authors.initials: AD
authors.lastname: Theocharis
authors.forename: D
authors.initials: D
authors.lastname: Kletsas
authors.forename: G N
authors.initials: GN
authors.lastname: Tzanakakis
authors.forename: N K
authors.initials: NK
authors.lastname: Karamanos
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051926:Basigin / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics; D000077544:Panitumumab; D053671:Syndecan-4 / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C497886:BSG protein, human; C508304:SDC4 protein, human; D053671:Syndecan-4; D051926:Basigin; D004815:Epidermal Growth Factor; D000077544:Panitumumab; D066246:ErbB Receptors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14