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: Guido M Sclabas, Tadashi Uwagawa, Christian Schmidt, Kenneth R Hess, Douglas B Evans, James L Abbruzzese, Paul J Chiao
• Journal: Cancer (Cancer) Vol. 103 Issue 12 Pg. 2485-90 (Jun 15 2005) ISSN: 0008-543X [Print] United States
• PMID: 15861417 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2005 American Cancer Society.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Membrane Proteins
• NF-kappa B
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Aspirin

Topics

• Adenocarcinoma (genetics, metabolism, prevention & control)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Aspirin (therapeutic use)
• Cyclooxygenase 2
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Proteins
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism, prevention & control)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Tumor Cells, Cultured