Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin.
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.
Sclabas, GM; Uwagawa, T; Schmidt, C; Hess, KR; Evans, DB; Abbruzzese, JL; Chiao, PJ
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