title: Ultraviolet enhances the sensitivity of pancreatic cancer cells to gemcitabine by activation of 5' AMP-activated protein kinase.
abstract: Although gemcitabine is recognized as the standard drug for the treatment of advanced pancreatic cancer, the clinical outcome is not satisfactory. We recently reported that relatively high dose ultraviolet-C (UV-C; 200J) inhibits cell growth by desensitization of epidermal growth factor receptor (EGFR) in human pancreatic cancer cells. In the present study, we investigated the combination effects of low dose UV-C (10J) and gemcitabine on apoptosis and cell growth in these cells. UV-C enhanced gemcitabine-induced suppression of cell viability. In addition, the combination use clearly induced apoptosis, while neither UV-C nor gemcitabine alone did. Concurrently, combination use caused the decrease in the EGFR protein level and reduced EGF-induced activation of Akt pathway, subsequently resulting in accumulation of β-catenin. The order of the treatment with UV-C and gemcitabine did not affect their synergistic effects on apoptosis and cell growth. Interestingly, combination use synergistically induced phosphorylation of 5' AMP-activated protein kinase (AMPK) alpha at Thr172 and acetyl-CoA carboxylase at Ser79 as a downstream molecular target of AMPK. AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-riboside, induced apoptosis and suppressed cell growth in these cells, thus suggesting that combination effects of UV-C and gemcitabine is due to the activation of AMPK. Together, our findings could provide a new aspect of pancreatic cancer therapy.
authors.affiliation: Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. seijiadachi0123@gmail.com
authors.forename: Seiji
authors.initials: S
authors.lastname: Adachi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yasuda
authors.forename: Junji
authors.initials: J
authors.lastname: Kawaguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakashima
authors.forename: Masahiko
authors.initials: M
authors.lastname: Itani
authors.forename: Momoko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D014466:Ultraviolet Rays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D000093542:Gemcitabine