The present study investigated the mechanisms involved in the mitogenic action of epidermal growth factor (EGF) in cultured human myometrial smooth muscle cells. The cells contained EGF/transforming growth factor-α (TGF-α) receptors as well as EGF and TGF-α mRNA transcripts and the corresponding proteins. Culturing with human EGF resulted in concentration- and time-dependent increases in cell density. The maximal increase was seen at 1 nm followed by a decrease to control levels at 100 nm EGF. The EGF increased cell density from 4 to 8 days followed by a plateau coinciding with the cells reaching confluence. EGF treatment concomitantly decreased the average size of cells. TGF-α mimicked EGF and there was no synergism between the two, suggesting a common mechanism of action. Although the presence of 10% fetal bovine serum enhanced overall cell growth, it was not required for EGF and TGF-α action. The receptor antibody, which is directed against the extracellular domain and can inhibit ligand binding to the receptors, dramatically inhibited the basal cell growth and exogenous EGF reversed the antibody effect. While TGF-α antibody was only marginally effective, EGF antibody had no effect on basal cell growth. Lavendustin (a tyrosine kinase inhibitor), calphostin (a protein kinase C inhibitor), but not H-89 (a protein kinase A inhibitor), inhibited EGF action. Indomethacin, a cyclo-oxygenase inhibitor, completely inhibited, whereas nordihydroguaiaretic acid, a lipoxygenase inhibitor, slightly inhibited EGF action. While estradiol-17β modestly inhibited basal as well as EGF-stimulated myometrial smooth muscle cell density, progesterone had no effect.
In summary, mitogenic action of EGF in human myometrial smooth muscle cells does not require serum components and it involves tyrosine kinase and protein kinase C signaling and eicosanoids from the cyclo-oxygenase pathway of arachidonic acid metabolism.
Journal of Endocrinology (1995) 146, 261–270
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