title: Gamma-secretase complexes regulate the responses of human pancreatic ductal adenocarcinoma cells to taxanes.
abstract: OBJECTIVE
  It was previously reported that γ-secretase inhibitors (GSIs) enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. To enable the development of taxane-based chemotherapy for pancreatic ductal adenocarcinoma (PDAC), this study investigated the molecular mechanisms by which γ-secretase (GS) complexes regulate taxane sensitivity.
  
  
  METHODS
  The effect of GS complexes on taxane-induced apoptosis in PDAC cells was evaluated by a cell cycle analysis. GS complexes were examined with small interference RNAs targeted to GS complex-related genes.
  
  
  RESULTS
  GSIs and silencing of presenilin 1 (PS1) did not affect cell proliferation but resulted in enhanced taxane-induced G(2)/M accumulation and apoptosis. Silencing of the Notch gene did not induce these effects. However, PS2-specific silencing suppressed proliferation and taxane-induced apoptosis.
  
  
  CONCLUSIONS
  Data from this study indicate that GS complexes regulate the response of PDAC to taxanes through GS-dependent and GS-independent mechanisms.
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Tasaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hideya
authors.initials: H
authors.lastname: Onishi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Katano
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053766:Presenilin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D043823:Taxoids; D053829:Amyloid Precursor Protein Secretases