Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2.
Hepatocellular carcinoma (HCC) is a common human cancer with high mortality, and currently, there is no effective chemoprevention or systematic treatment. Recent evidence suggests that cyclooxygenase-2 (COX-2)-derived PGE(2) and Wnt/beta-catenin signaling pathways are implicated in hepatocarcinogenesis. Here, we report that omega-3 polyunsaturated fatty acids (PUFA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) inhibit HCC growth through simultaneously inhibition of COX-2 and beta-catenin. DHA and EPA treatment resulted in a dose-dependent reduction of cell viability with cleavage of poly ADP ribose polymerase, caspase-3, and caspase-9 in three human HCC cell lines (Hep3B, Huh-7, HepG2). In contrast, AA, a omega-6 PUFA, exhibited no significant effect. DHA and EPA treatment caused dephosphorylation and thus activation of GSK-3beta, leading to beta-catenin degradation in Hep3B cells. The GSK-3beta inhibitor, LiCl, partially prevented DHA-induced beta-catenin protein degradation and apoptosis. Additionally, DHA induced the formation of beta-catenin/Axin/GSK-3beta binding complex, which serves as a parallel mechanism for beta-catenin degradation. Furthermore, DHA inhibited PGE(2) signaling through downregulation of COX-2 and upregulation of the COX-2 antagonist, 15-hydroxyprostaglandin dehydrogenase. Finally, the growth of HCC in vivo was significantly reduced when mouse HCCs (Hepa1-6) were inoculated into the Fat-1 transgenic mice, which express a Caenorhabditis elegans desaturase converting omega-6 to omega-3 PUFAs endogenously. These findings provide important preclinical evidence and molecular insight for utilization of omega-3 PUFAs for the chemoprevention and treatment of human HCC.
Lim
Kyu
K
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. kyulim@cnu.ac.kr
Han
Chang
C
Dai
Yifan
Y
Shen
Miaoda
M
Wu
Tong
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D060466:Axin Protein; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis; D018021:Lithium Chloride / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D060466:Axin Protein; D052246:Cyclooxygenase 2 Inhibitors; D005231:Fatty Acids, Unsaturated; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D015232:Dinoprostone