GROWTH-INHIBITION OF HUMAN LUNG ADENOCARCINOMA CELLS BY ANTIBODIES AGAINST EPIDERMAL GROWTH-FACTOR RECEPTOR AND BY GANGLIOSIDE G(M3) - INVOLVEMENT OF RECEPTOR-DIRECTED PROTEIN-TYROSINE PHOSPHATASE(S)

Growth of the EGF receptor-expressing non-small-cell lung carcinoma ce ll line H125 seems to be at least partially driven by autocrine activa tion of the resident EGF receptors. Thus, the possibility of an EGF re ceptor-directed antiproliferative treatment was investigated in vitro using a monoclonal antibody (alpha EGFR ior egf/r3) against the human EGF receptor and gangliosides which are known to possess antiprolifera tive and anti-tyrosine kinase activity. The moderate growth-inhibitory effect of alpha EGFR ior egf/r3 was strongly potentiated by the addit ion of monosialoganglioside G(M3). Likewise, the combination of alpha EGFR ior egf/r3 and G(M3) inhibited EGF receptor autophosphorylation a ctivity in H125 cells more strongly than either agent alone. A synergi stic inhibition of EGF receptor autophosphorylation by alpha EGFR ior egf/r3 and G(M3) was also observed in the human epidermoid carcinoma c ell line A431. In both cell lines, the inhibition of EGF receptor auto phosphorylation by G(M3) was prevented by pretreatment of the cells wi th pervanadate, a potent inhibitor of protein tyrosine phosphatases (P TPases). Also, G(M3) accelerated EGF receptor dephosphorylation in iso lated A431 cell membranes. These findings indicate that G(M3) has the capacity to activate EGF receptor-directed PTPase activity and suggest a novel possible mechanism for the regulation of cellular PTPases.