Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K

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dc.contributor.author Cheng, Z.
dc.contributor.author Surichan, Somchaiya
dc.contributor.author Ruparelia, K. C.
dc.contributor.author Arroo, R. R. J.
dc.contributor.author Boarder, M. R.
dc.date.accessioned 2011-09-06T11:10:35Z
dc.date.available 2011-09-06T11:10:35Z
dc.date.issued 2011
dc.identifier.citation Cheng, Z. (2011) Tangeretin and its metabolite 4 '-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K. British Journal of Pharmacology, 162 (8), pp. 1781-1791 en
dc.identifier.issn 1476-5381
dc.identifier.uri http://hdl.handle.net/2086/5198
dc.description.abstract The mechanisms by which the dietary compound tangeretin has anticancer effects may include acting as a prodrug, forming an antiproliferative product in cancer cells. Here we show that tangeretin also inhibits cell cycle progression in hepatocytes and investigate the role of its primary metabolite 4'-hydroxy-5,6,7,8-tetramethoxyflavone (4'-OH-TMF) in this effect. EXPERIMENTAL APPROACH We used epidermal growth factor (EGF)-stimulated rat hepatocytes, with [(3)H]-thymidine incorporation into DNA as an index of progression to S-phase of the cell cycle, and Western blots for phospho-proteins involved in the cell signalling cascade. KEY RESULTS Incubation of tangeretin with microsomes expressing CYP1A, or with hepatocytes, generated a primary product we identified as 4'-OH-TMF. Low micromolar concentrations of tangeretin or 4'-OH-TMF gave a concentration-dependent inhibition of EGF-stimulated progression to S-phase while having little effect on cell viability. To determine whether time for conversion of tangeretin to an active metabolite would enhance the inhibitory effect we used long pre-incubations; this reduced the inhibitory effect, in parallel with a reduction in the concentration of tangeretin. The EGF-stimulation of hepatocyte cell cycle progression requires signalling through Akt/mTOR/p70S6K kinase cascades. The tangeretin metabolite 4'-OH-TMF selectively inhibited S6K phosphorylation in the absence of significant inhibition of upstream Akt activity, suggesting an effect at the level of mTOR. CONCLUSIONS AND IMPLICATIONS Tangeretin and 4'-OH-TMF both inhibit cell cycle progression in primary hepatocytes. The inhibition of p70S6K phosphorylation by 4'-OH-TMF raises the possibility that inhibition of the mTOR pathway may contribute to the anticancer influence of a flavonoid-rich diet. en
dc.language.iso en en
dc.publisher Wiley en
dc.subject citrus flavone tangeretin en
dc.subject cultured rat hepatocytes en
dc.subject in-vitro en
dc.subject carcinoma cells en
dc.subject cancer cells en
dc.subject human breast en
dc.subject expression en
dc.subject growth en
dc.subject activation en
dc.subject AKT en
dc.title Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K en
dc.type Article en
dc.identifier.doi http://dx.doi.org/10.1111/j.1476-5381.2010.01185.x
dc.researchgroup Chemistry for Health
dc.peerreviewed Yes en


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