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Abstract
BackgroundEndometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. At the molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Six different human uterine cancer cell lines were used as a model (HeLa, Hec-1A, KLE, RL95-2, Ishikawa and EN-1078D).Results and discussionHigh-dose of resveratrol triggered apoptosis in five out of six uterine cancer cell lines, as judged from Hoechst nuclear staining and effector caspase cleavage. In accordance, uterine cancer cell proliferation was decreased. Resveratrol also reduced cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT. Endogenous COX-2 protein levels were decreased, concomitant with a decrease in production of COX metabolites PGE2 and PGF2α, in each uterine cancer cell line expressing detectable levels of COX-1 and/or COX-2 in presence of resveratrol. Although COX expression was identified as a target of resveratrol in uterine cancer cells, inhibition of COX activity or exogenously added PGE2 did not modulate the effect of resveratrol on cellular proliferation.ConclusionHigh-dose of resveratrol exerts tumoricidal activity over uterine cancer cells and regulates COX expression. In these cells, resveratrol would not directly target COX activity, but possibly other enzymes involved in prostaglandin synthesis that act downstream of the COXs.
Highlights
Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world
Similar to COX-2, COX-1 is up-regulated in different carcinomas [16,17] and plays a role in tumorigenesis [18,19]; COX-1 is present in endometrial tumors [20]
Resveratrol interferes with AKT survival pathway in uterine cancer cells Resveratrol has been reported to inhibit AKT activation [37,38], and we have previously demonstrated that the activity of AKT directly modulated survival/apoptosis in uterine cancer cells [8]
Summary
Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. Resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Expression of COX-2 notably confers resistance to apoptosis [8]. Similar to COX-2, COX-1 is up-regulated in different carcinomas [16,17] and plays a role in tumorigenesis [18,19]; COX-1 is present in endometrial tumors [20]. The synthesis of PGE2 would be key elements in the pathophysiology of different cancers [23,24]; notably, PGE2 exerts immunosuppressive [25,26] as well as proangiogenic [27,28] activities
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