EGF-DEPENDENT AND INDEPENDENT PROGRAMMED CELL-DEATH PATHWAYS IN NCI-H596 NONSMALL CELL LUNG-CANCER CELLS

EGF receptor (EGFR) is a transmembrane glycoprotein with tyrosine kina se activity that is overexpressed in many human cancers, including lun g. In the present study, we evaluated the effect of EGF and genistein, a tyrosine kinase inhibitor, on cell proliferation, EGFR phosphorylat ion and its downstream signal MAP kinase activation and investigated t he involvement of these processes in programmed cell death in a human pulmonary adenosquamous carcinoma cell line, NCI-H596. Treatment with EGF resulted in phosphorylation of EGFR, activation of MAP kinase, pho sphorylation of ERK 2 (an isoform of MAP kinase), increased cell proli feration and induction of cross-linked envelope (CLE) competence. Geni stein abolished the ability of EGF to induce EGFR phosphorylation, to activate MAP kinase and to increase cell proliferation. Genistein alon e stimulated CLE competence, but apparently by a different mechanism t han EGF since genistein prevented EGF-stimulated CLE competence. The g enistein-stimulated CLE competence was accompanied by a decrease in ce ll proliferation and increased DNA fragmentation. These results demons trate that genistein antagonizes growth stimulatory EGF signaling upst ream of MAP kinase and may simultaneously stimulate an apoptotic pathw ay. Furthermore, EGF appears to stimulate an alternate, growth related programmed cell death pathway, not involving DNA fragmentation, but c haracterized by rapid proliferation and genistein-sensitive CLE compet ence. (C) 1998 Academic Press.