title: Alteration of the intrinsic apoptosis pathway is involved in Notch-induced chemoresistance to gemcitabine in pancreatic cancer.
abstract: OBJECTIVE
  Chemoresistance is a major challenge in pancreatic cancer (PC) treatment. Limited data have shown that members of the Notch signaling pathway are involved in resistance to gemcitabine (GEM) in PC. However, further evidence is needed and the underlying mechanisms remain to be elucidated. The current study aims to investigate the role of alterations of the intrinsic apoptosis pathway in Notch-induced GEM resistance of PC.
  
  
  METHODS
  The Notch signaling pathway was inhibited or activated in three PC cell lines (AsPC-1, BxPC-3, and MIA PaCa-2) by γ-secretase inhibition and Notch intracellular domain (NICD) overexpression, respectively. Subsequent analyses included inhibition rates of cell proliferation by GEM, cell apoptosis, and expression of proteins involved in the intrinsic apoptosis pathway.
  
  
  RESULTS
  Hes-1 expression was significantly elevated after GEM treatment, indicating Notch activation. Inhibition of the Notch signaling pathway by DAPT, a γ-secretase inhibitor, resulted in a significant increase of the inhibition rates by GEM in all PC cell lines. In addition, there was more frequent apoptosis, higher caspase-3 activity, up-regulation of Bax, and down-regulation of Bcl-2 and Bcl-xL. Conversely, transient transfection of NICD, which enhances the activity of the Notch signaling, caused a remarkable decrease of the chemosensitivity to GEM.
  
  
  CONCLUSIONS
  An alteration of the intrinsic apoptosis pathway is involved in Notch-induced chemoresistance to GEM in PC cells.
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Xiao
authors: X
authors: Du
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China; National Laboratory of Medical Molecular Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China. Electronic address: zhao8028@263.net.
authors: Yu-Pei
authors: YP
authors: Zhao
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Tai-Ping
authors: TP
authors: Zhang
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Li
authors: L
authors: Zhou
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Ge
authors: G
authors: Chen
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Tian-Xiao
authors: TX
authors: Wang
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Lei
authors: L
authors: You
authors: Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
authors: Hong
authors: H
authors: Shu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch; D003841:Deoxycytidine; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D000093542:Gemcitabine
keywords: Chemoresistance; Gemcitabine; Intrinsic apoptosis pathway; Notch; Pancreatic cancer