title: Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin.
abstract: BACKGROUND
  Pancreatic carcinoma exhibits a unique genetic profile of mutations that may play key roles in its progression to malignant phenotypes. Constitutive activation of transcription factor nuclear factor kappa B (NF-kappaB) is a frequent molecular alteration in pancreatic carcinoma, suggesting a possible link between inflammation and cancer. The aims of the current study were to determine the effects of aspirin on pancreatic carcinoma prevention and to reveal a possible mechanism of aspirin-mediated cancer chemoprevention.
  
  
  METHODS
  An orthotopic mouse model with human pancreatic carcinoma cell lines PANC-1, PANC-1/Puro, and PANC-1/IkappaBalphaM was used to study the inhibitory effects of aspirin on pancreatic tumor formation.
  
  
  RESULTS
  Aspirin inhibited constitutive NF-kappaB activity in culture and, in turn, decreased the expression of the NF-kappaB downstream target gene, Cox-2, in PANC-1 or PANC-1/Puro cells, without significantly inhibiting the in vitro growth of PANC-1/Puro cells. All animals inoculated with either PANC-1 or PANC-1/Puro cells, and not given aspirin, developed pancreatic tumors, whereas none of the mice injected with PANC-1/IkappaBalphaM cells showed any evidence of pancreatic tumor formation. Animals given aspirin for 6 days before, or at the time of, orthotopic tumor cell injection showed a significantly lower incidence of tumor formation compared with those receiving aspirin 2 weeks after inoculation and controls receiving no aspirin.
  
  
  CONCLUSIONS
  Aspirin repressed tumor formation by PANC-1 cells in vivo in a prophylactic setting, suggesting a possible mechanism for aspirin's preventive effect in pancreatic carcinoma through inhibition of NF-kappaB activation and a mechanistic link between inflammation and tumorigenesis. Aspirin-mediated antiinflammatory approaches might be an effective strategy to prevent pancreatic carcinoma.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Guido M
authors.initials: GM
authors.lastname: Sclabas
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Evans
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; D016328:NF-kappa B; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin