Ligand-like effects induced by anti-c-erbB-2 antibodies do not correlate with and are not required for growth inhibition of human carcinoma cells.
The c-erbB-2 gene encodes a M(r) 185,000 tyrosine kinase receptor (p185) with extensive homology to the epidermal growth factor receptor. We have conducted mechanistic studies with several anti-p185 monoclonal antibodies (TAb 250, -255, -257, -260, and -263) directed against the extracellular domain of p185 utilizing the SKBR-3, BT-474, and SKOV-3 cancer cell lines. Several of these antibodies exhibited ligand-mimicking properties: they induced tyrosine phosphorylation of p185; increased the catalytic activity of the receptor substrate phospholipase C-gamma 1; exhibited time- and pH-dependent internalization; induced receptor down-regulation; and increased the turnover of the p185 protein delta 3-fold. However, there was not a universal correlation between the antibody-mediated ligand-like effects and growth inhibition. TAb 250 inhibited BT-474 cells but did not alter p185 phosphotyrosine content or increase receptor turnover in these cells. TAb 260 increased p185 protein turnover but did not affect proliferation of the SKOV-3 cell line. Furthermore, blockade of TAb 250-induced receptor phosphorylation with the tyrosine kinase inhibitor tyrphostin 50864-2 did not abrogate TAb 250-mediated growth inhibition of SKBR-3 cells. These data suggest that ligand-like effects mediated by p185 antibodies are not critical for the growth inhibition of c-erbB-2-overexpressing carcinoma cells.
Shawver
L K
LK
Department of Cell Biology and Immunology, Berlex Biosciences, Richmond, California 94804.
Mann
E
E
Elliger
S S
SS
Dugger
T C
TC
Arteaga
C L
CL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000276:immunology* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D007457:Iodine Radioisotopes; D008024:Ligands; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D010738:Type C Phospholipases