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 systems. To identify the mechanisms by which cells enhance their proliferative 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. Both EGF and IR induced EGFR autophosphorylation, comparable levels of phospholipase C gamma activation as measured by inositol-1,4,5-triphosphate production, and as a consequence oscillations in cytosolic [Ca2+]. Activities of Raf-1 and mitogen-activated protein kinase (MAPK) were also stimulated by EGF and IR by Ca(2+)-dependent mechanisms. All these responses to EGF and IR were dependent upon activation of EGFR as judged by the use of the specific inhibitor of EGFR autophosphorylation, tyrphostin AG1478. Importantly, IR-induced proliferation of A431 cells was also inhibited by AG1478. This is the first report which demonstrates a link between IR-induced activation of proliferative signal transduction pathways and enhanced proliferation. We propose that accelerated repopulation of tumors whose growth is regulated by EGFR is initiated by an IR-induced EGFR activation mechanism that mimics the effects of growth factors.
Schmidt-Ullrich
R K
RK
Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0058, USA.
Mikkelsen
R B
RB
Dent
P
P
Todd
D G
DG
Valerie
K
K
Kavanagh
B D
BD
Contessa
J N
JN
Rorrer
W K
WK
Chen
P B
PB
D001943:Breast Neoplasms / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D004789:Enzyme Activation / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D051966:Phospholipase C gamma; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D011799:Quinazolines / Q000494:pharmacology; D011839:Radiation, Ionizing; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D020032:Tyrphostins
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D019000:Phosphotyrosine; D015544:Inositol 1,4,5-Trisphosphate; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium