title: Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells.
abstract: Gemcitabine, an antitumor drug, is currently considered to be the standard of care for the treatment of advanced pancreatic cancer, but the clinical outcome is still not satisfactory. Although heat shock protein (HSP) 27 is implicated in the resistance to chemotherapy in several types of cancers, the precise role of phosphorylated HSP27 in cancer cells remains to be clarified. In this study, we investigated the relationship between the effect of gemcitabine and the phosphorylation status of HSP27 in pancreatic cancer cells, Panc1 and KP3. Gemcitabine suppressed pancreatic cancer cell growth and induced apoptosis. Gemcitabine caused activation of p38 mitogen-activated protein kinase (MAPK), MAPK-activated protein kinase 2 (MAPKAPK-2) and subsequently phosphorylation of HSP27 at Ser15, 78 and 82 without affecting total HSP27 levels. The inhibitions of p38 MAPK and MAPKAPK-2 reduced the phosphorylation of HSP27 and apoptosis in gemcitabine-treated cells. To further investigate the role of phosphorylated HSP27, we established Panc1 cell lines which were stably transfected with empty vector (empty cells), wild-type HSP27-encoding vector (WT cells) and 2 mutant HSP27-encoding vectors that mimic non-phosphorylated (3A), and phosphorylated (3D), respectively. In comparison of empty cells with WT cells, there was no difference in cell growth rate and the sensitivity to gemcitabine. Interestingly, cell growth of 3D cells was retarded as compared to that of 3A cells. Taken together, our results strongly suggest that phosphorylation status of HSP27 plays a key role in gemcitabine-induced growth suppression of pancreatic cancer.
authors: Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors: Masanori
authors: M
authors: Nakashima
authors: Seiji
authors: S
authors: Adachi
authors: Ichiro
authors: I
authors: Yasuda
authors: Takahiro
authors: T
authors: Yamauchi
authors: Junji
authors: J
authors: Kawaguchi
authors: Masahiko
authors: M
authors: Itani
authors: Takashi
authors: T
authors: Yoshioka
authors: Rie
authors: R
authors: Matsushima-Nishiwaki
authors: Yoshinobu
authors: Y
authors: Hirose
authors: Osamu
authors: O
authors: Kozawa
authors: Hisataka
authors: H
authors: Moriwaki
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018832:Molecular Chaperones; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093542:Gemcitabine; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases; D000093542:Gemcitabine; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human