title: Autophagy is needed for the growth of pancreatic adenocarcinoma and has a cytoprotective effect against anticancer drugs.
abstract: OBJECTIVE
  Autophagy is a regulated process of degradation and recycling of cellular constituents. The role of autophagy in pancreatic cancer is still not clear. Some studies indicate that in pancreatic cancer autophagy exerts cytoprotective effects, whereas others suggest that autophagy positively contributes to cell death by enhancing cytotoxicity of anticancer drugs. The aim of this study was to investigate the role of autophagy in pancreatic cancer, and to provide insights into new strategies for treatment.
  
  
  METHODS
  Pancreatic cancer cell lines PANC-1 and BxPC-3 were treated with anticancer drugs (5-fluorouracil or gemcitabine) alone and in combination with autophagy inhibitors (chloroquine or wortmannin). Biopsy samples were retrieved from patients from pancreatic normal tissue and adenocarcinoma. Western blot of microtubule-associated protein 1 light chain 3 (LC3)-II was performed to investigate the degree of autophagy and cell proliferation was assessed by a crystal violet assay.
  
  
  RESULTS
  Autophagy was active in PANC-1 cells under basal conditions. Autophagy was significantly induced in pancreatic ductal adenocarcinoma compared to healthy pancreatic tissue in patients. Inhibition of autophagy by chloroquine suppressed the growth of PANC-1 and BxPC-3. Autophagy was markedly increased after treatment with 5-fluorouracil or gemcitabine. Inhibition of autophagy by chloroquine potentiated the inhibition of cell proliferation of PANC-1 and BxPC-3 by 5-fluorouracil and gemcitabine.
  
  
  CONCLUSIONS
  Our results with pancreatic cancer cell lines and human pancreatic adenocarcinoma suggest that autophagy contributes to pancreatic cancer cell growth. Autophagy has a cytoprotective effect against 5-fluorouracil and gemcitabine in pancreatic cancer cells. Combination therapy of these anticancer drugs and chloroquine should be investigated.
authors: Tampere Pancreas Laboratory, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, P.O. Box 2000, 33521 Tampere, Finland; Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Daisuke
authors: D
authors: Hashimoto
authors: Tampere Pancreas Laboratory, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, P.O. Box 2000, 33521 Tampere, Finland.
authors: Merja
authors: M
authors: Bläuer
authors: Department of Surgery, Kumamoto Regional Medical Center, 5-16-10 Honjo, Kumamoto 860-0811, Japan.
authors: Masahiko
authors: M
authors: Hirota
authors: Tampere Pancreas Laboratory, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, P.O. Box 2000, 33521 Tampere, Finland.
authors: Niina H
authors: NH
authors: Ikonen
authors: Tampere Pancreas Laboratory, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, P.O. Box 2000, 33521 Tampere, Finland.
authors: Juhani
authors: J
authors: Sand
authors: Tampere Pancreas Laboratory, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, P.O. Box 2000, 33521 Tampere, Finland. Electronic address: johanna.laukkarinen@fimnet.fi.
authors: Johanna
authors: J
authors: Laukkarinen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077191:Wortmannin; D000093542:Gemcitabine
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; D002738:Chloroquine; D005472:Fluorouracil; D000077191:Wortmannin; D000093542:Gemcitabine
keywords: 5-Fluorouracil; Autophagy; BxPC-3; Chemotherapy; Chloroquine; Gemcitabine; LC3; PANC-1; Pancreatic cancer; Wortmannin