title: Resistance to gemcitabine in the pancreatic cancer cell line KLM1-R reversed by metformin action.
abstract: OBJECTIVE
  The pancreatic cancer cell line KLM1 can gain chemoresistance following gemcitabine (GEM) treatment. Metformin was found to be a useful sensitising agent towards GEM treatment following gain of chemoresistance.
  
  
  METHODS
  The proliferation of GEM-sensitive and -resistant cells was investigated over a range of metformin concentrations from 0.005 to 5 mM. The intra- and extra-cellular energetic profiles of these two cell types under metformin exposure were investigated through adenosine triphosphate (ATP) and L-lactate assays.
  
  
  RESULTS
  There was an unexpected decrease in intracellular L-lactate following gain of chemoresistance, despite observable medium acidification. At the biochemical level, a marked effect on phosphorylated proteins upstream of Akt, along the mTOR pathway, was observed at 6 h. These changes followed a time-dependent pattern linked closely to the changes in the energetic profile.
  
  
  CONCLUSIONS
  Together, these results indicate that metformin indirectly blocks protein phosphorylation, including that of heat shock protein 27 (HSP27).
authors: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Japan Department of Anatomy and Cell Biology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta angenlabs@gmail.com.
authors: Byron
authors: B
authors: Baron
authors: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors: Yufeng
authors: Y
authors: Wang
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Shin-Ichiro
authors: S
authors: Maehara
authors: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yoshihiko
authors: Y
authors: Maehara
authors: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors: Yasuhiro
authors: Y
authors: Kuramitsu
authors: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Japan Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan-shi, Japan.
authors: Kazuyuki
authors: K
authors: Nakamura
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D018832:Molecular Chaperones; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D003841:Deoxycytidine; D008687:Metformin; D000093542:Gemcitabine
keywords: HSP27; metformin; pancreatic cancer