Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2016-11, Vol.9 (11), p.855-865
• Main Authors: Boutaud, Olivier, Sosa, I Romina, Amin, Taneem, Oram, Denise, Adler, David, Hwang, Hyun S, Crews, Brenda C, Milne, Ginger, Harris, Bradford K, Hoeksema, Megan, Knollmann, Bjorn C, Lammers, Philip E, Marnett, Lawrence J, Massion, Pierre P, Oates, John A
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aspirin - pharmacology; Cell Line, Tumor; Cyclooxygenase 2 - drug effects; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - biosynthesis; Female; Humans; Male; Neoplasm Invasiveness - pathology
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.capr-16-0094

Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E (PGE ) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE biosynthesis. We show that low-dose aspirin inhibits systemic PGE biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.