Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene A₄hydrolase.
The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4'-trihydroxy-trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A(4) hydrolase (LTA(4)H) as a relevant target in pancreatic cancer. LTA(4)H knockdown limited the formation of leukotriene B(4) (LTB(4)), the enzymatic product of LTA(4)H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA(4)H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA(4)H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB(4) production and expression of the LTB(4) receptor 1 (BLT(1)). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA(4)H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA(4)H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA(4)H activity. Our findings identify LTA(4)H as a functionally important target for mediating the anticancer properties of resveratrol.
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Naomi
N
Oi
Chul-Ho
CH
Jeong
Janos
J
Nadas
Yong-Yeon
YY
Cho
Angelo
A
Pugliese
Ann M
AM
Bode
Zigang
Z
Dong
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology; D059808:Polyphenols; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014920:Wine; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D013267:Stilbenes; D007975:Leukotriene B4; D004851:Epoxide Hydrolases; D000077185:Resveratrol; C043134:leukotriene A4 hydrolase