title: 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 in human pancreatic cancer and is one of the clinical targets in its treatment. In the present study we investigated the mechanism underlying ultraviolet C (UVC)-radiation-induced cell growth inhibition and downregulation of EGFR in human pancreatic cancer cells (Panc1 and KP3). The cell proliferation assay indicated that Panc1 and KP3 cells were more sensitive to UVC radiation, and their growth was significantly inhibited compared to cells of the normal human pancreatic epithelial cell line, PE. Although EGFR levels was extremely low in PE cells, EGFR were highly overexpressed in Panc1 and KP3 cells, and UVC radiation downregulated the expression of EGFR in a time-dependent manner and induced phosphorylation of EGFR at Ser1046/1047 (S1046/7) in Panc1 and KP3 cells. UVC radiation induced activation of p38 mitogen-activated protein kinase (MAPK), and EGFR phosphorylation at S1046/7 induced by UVC radiation was markedly attenuated by the inhibition of p38 MAPK. Moreover, fluorescence microscopy revealed that p38 MAPK activated by UVC radiation triggered EGFR internalization and that this was not correlated with c-Cbl, an ubiquitin ligase, which plays an important role in EGF-induced EGFR downregulation. Taken together, our results suggest that in pancreatic cancer cells UVC radiation induced desensitization of the cells to EGFR stimuli via phosphorylation of EGFR at S1046/7 by activation of p38 MAPK, independent of c-Cbl.
authors.affiliation: Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Adachi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yasuda
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakashima
authors.forename: Junji
authors.initials: J
authors.lastname: Kawaguchi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nishii
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Yukio
authors.initials: Y
authors.lastname: Okano
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hirose
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects*; D004789:Enzyme Activation / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation / Q000528:radiation effects; D021381:Protein Transport / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D012694:Serine; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases