UVC radiation induces downregulation of EGF Receptor via phosphorylation at serine 1046/1047 in human pancreatic cancer cells

Abstract

Epidermal growth factor receptor (EGFR) is overexpressed inhuman pancreatic cancer and is one of the clinical targets in itstreatment. In the present study we investigated the mechanismunderlying ultraviolet C (UVC)-radiation-induced cell growthinhibition and downregulation of EGFR in human pancreaticcancer cells (Panc1 and KP3). The cell proliferation assayindicated that Panc1 and KP3 cells were more sensitive to UVCradiation, and their growth was significantly inhibited comparedto cells of the normal human pancreatic epithelial cell line, PE.Although EGFR levels was extremely low in PE cells, EGFRwere highly overexpressed in Panc1 and KP3 cells, and UVCradiation downregulated the expression of EGFR in a timedependentmanner and induced phosphorylation of EGFR atSer1046/1047 (S1046/7) in Panc1 and KP3 cells. UVC radiationinduced activation of p38 mitogen-activated protein kinase(MAPK), and EGFR phosphorylation at S1046/7 induced byUVC radiation was markedly attenuated by the inhibition of p38MAPK. Moreover, fluorescence microscopy revealed that p38MAPK activated by UVC radiation triggered EGFR internalizationand that this was not correlated with c-Cbl, an ubiquitinligase, which plays an important role in EGF-induced EGFRdownregulation. Taken together, our results suggest that inpancreatic cancer cells UVC radiation induced desensitizationof the cells to EGFR stimuli via phosphorylation of EGFRat S1046/7 by activation of p38 MAPK, independent of c-Cbl. © 2011 by Radiation Research Society.