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
Guido M
GM
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Uwagawa
Tadashi
T
Schmidt
Christian
C
Hess
Kenneth R
KR
Evans
Douglas B
DB
Abbruzzese
James L
JL
Chiao
Paul J
PJ
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
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