ROLE OF HEPARIN-BINDING EGF-RELATED PEPTIDES IN PROLIFERATION AND APOPTOSIS OF ACTIVATED RAS-STIMULATED INTESTINAL EPITHELIAL-CELLS

The ras mutation is a common and critical step in carcinogenesis. Auto crine growth factors are also known to play an important role in cance r cell growth and transformation. However, the contribution of autocri ne growth factors in regulation of proliferation and apoptosis of acti vated ras-stimulated intestinal epithelium is not fully understood. Th erefore, we constructed activated ras-transfected intestinal epithelia l cell clones (IEC-ras) to examine the role of epidermal growth factor (EGF)-related peptides in the behavior of IEC-ras. Overexpression of EGF family growth factors (transforming growth factor alpha, heparin-b inding EGF-like growth factor, amphiregulin and betacellulin) and stro nger phosphorylation of the EGF receptor was observed in IEC-ras compa red with control cells. IEC-ras proliferated move rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG1478, abolishe d the increased proliferation of IEC-ras. Heparitinase and chlorate al so prevented increased proliferation of IEC-ras. Additionally, IEC-ras expressed more bcl-2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG1478 suppressed bcl-2 expression and inhibited resistance to apoptosis of IEC-ras. Heparitinase and chlorat e had effects similar to those of AG1478. Our data indicate that hepar in-binding EGF family growth factors play an important role in both in creased proliferation and resistance to apoptosis of ras-stimulated in testinal epithelial cells. (C) 1997 Wiley-Liss, Inc.