Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation.
The beneficial effects of omega-3 fatty acids are believed to be due in part to selective alteration of arachidonate metabolism that involves cyclooxygenase (COX) enzymes. Here we investigated the effect of eicosapentaenoic acid (EPA) on the proliferation of human non-small cell lung cancer A549 (COX-2 over-expressing) and H1299 (COX-2 null) cells as well as their xenograft models. While EPA inhibited 50% of proliferation of A549 cells at 6.05 µM, almost 80 µM of EPA was needed to reach similar levels of inhibition of H1299 cells. The formation of prostaglandin (PG)E3 in A549 cells was almost threefold higher than that of H1299 cells when these cells were treated with EPA (25 µM). Intriguingly, when COX-2 expression was reduced by siRNA or shRNA in A549 cells, the antiproliferative activity of EPA was reduced substantially compared to that of control siRNA or shRNA transfected A549 cells. In line with this, dietary menhaden oil significantly inhibited the growth of A549 tumors by reducing tumor weight by 58.8 ± 7.4%. In contrast, a similar diet did not suppress the development of H1299 xenograft. Interestingly, the ratio of PGE3 to PGE2 in A549 was about 0.16 versus only 0.06 in H1299 xenograft tissues. Furthermore, PGE2 up-regulated expression of pAkt, whereas PGE3 downregulated expression of pAkt in A549 cells. Taken together, the results of our study suggest that the ability of EPA to generate PGE3 through the COX-2 enzyme might be critical for EPA-mediated tumor growth inhibition which is at least partly due to down-regulation of Akt phosphorylation by PGE3.
Department of General Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
Peiying
P
Yang
Carrie
C
Cartwright
Diana
D
Chan
Jibin
J
Ding
Edward
E
Felix
Yong
Y
Pan
Jihai
J
Pang
Patrea
P
Rhea
Keith
K
Block
Susan M
SM
Fischer
Robert A
RA
Newman
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004032:Diet; D015232:Dinoprostone / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D016718:Arachidonic Acid; C033246:prostaglandin E3; D015118:Eicosapentaenoic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000527:Alprostadil; D015232:Dinoprostone
COX-2; NSCLC cells; antiproliferative activity; fish oil EPA; prostaglandins