Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene A4 hydrolase

Naomi Hamada, Chul Ho Jeong, Janos Nadas, Yong Yeon Cho, Angelo Pugliese, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxytrans-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 A4 hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA 4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol.

Original languageEnglish (US)
Pages (from-to)9755-9764
Number of pages10
JournalCancer Research
Volume70
Issue number23
DOIs
StatePublished - Dec 1 2010

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