title: HMGA1 is a molecular determinant of chemoresistance to gemcitabine in pancreatic adenocarcinoma.
abstract: OBJECTIVE
  HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. We previously have shown that RNA interference targeting the HMGA1 gene may represent a potential chemosensitizing strategy in pancreatic adenocarcinoma cells. In this study, we tested the hypothesis that HMGA1 promotes chemoresistance to gemcitabine in pancreatic cancer cells.
  
  
  RESULTS
  Stable short hairpin RNA-mediated HMGA1 silencing in BxPC3 and MiaPaCa2 cells promoted chemosensitivity to gemcitabine, with reductions in gemcitabine IC(50) and increases in gemcitabine-induced apoptosis and caspase-3 activation. In contrast, forced HMGA1 overexpression in MiaPaCa2 cells promoted chemoresistance to gemcitabine, with increases in gemcitabine IC(50) and reductions in gemcitabine-induced apoptosis and caspase-3 activation. Dominant negative Akt abrogated HMGA1 overexpression-induced increases in chemoresistance to gemcitabine. Finally, HMGA1 silencing promoted chemosensitivity to gemcitabine in vivo in a nude mouse xenograft model of pancreatic adenocarcinoma.
  
  
  CONCLUSIONS
  Our findings suggest that HMGA1 promotes chemoresistance to gemcitabine through an Akt-dependent mechanism. Targeted therapies directed at HMGA1 represent a potential strategy for ameliorating chemoresistance in pancreatic adenocarcinoma.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Siong-Seng
authors.initials: SS
authors.lastname: Liau
authors.forename: Edward
authors.initials: E
authors.lastname: Whang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000556:secondary; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D025741:HMGA1a Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D025741:HMGA1a Protein; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D000093542:Gemcitabine