RADIATION-INDUCED PROLIFERATION OF THE HUMAN A431 SQUAMOUS CARCINOMA-CELLS IS DEPENDENT ON EGFR TYROSINE PHOSPHORYLATION

Accelerated cellular repopulation has been described as a response of tumors to fractionated irradiation in both normal tissue and tumor sys tems, To identify the mechanisms by which cells enhance their prolifer ative rate in response to clinically used doses of ionizing radiation (IR) we have studied human mammary and squamous carcinoma cells which are autocrine growth regulated by the epidermal growth factor receptor (EGFR) and its ligands, transforming growth factor-alpha and EGF, Bot h EGF and IR induced EGFR autophosphorylation, comparable levels of ph ospholipase C gamma activation as measured by inositol-1,4,5-triphosph ate production, and as a consequence oscillations in cytosolic [Ca2+]. Activities of Raf-l and mitogen-activated protein kinase (MAPK) were also stimulated by EGF and IR by Ca2+-dependent mechanisms. All these responses to EGF and IR were dependent upon activation of EGFR as judg ed by the use of the specific inhibitor of EGFR autophosphorylation, t yrphostin AG1478. Importantly, IR-induced proliferation of A431 cells was also inhibited by AG1478. This is the first report which demonstra tes a link between IR-induced activation of proliferative signal trans duction pathways and enhanced proliferation, We propose that accelerat ed repopulation of tumors whose growth is regulated by EGFR is initiat ed by an IR-induced EGFR activation mechanism that mimics the effects of growth factors.