Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth

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buir.contributor.authorŞentürk, Şerif
buir.contributor.authorMumcuoğlu, Mine
buir.contributor.authorGürsoy-Yüzügüllü, Özge
buir.contributor.authorCingöz, Burcu
buir.contributor.authorAkçalı, Kamil Can
buir.contributor.authorÖztürk, Mehmet
dc.citation.epage974en_US
dc.citation.issueNumber3en_US
dc.citation.spage966en_US
dc.citation.volumeNumber52en_US
dc.contributor.authorŞentürk, Şerifen_US
dc.contributor.authorMumcuoğlu, Mineen_US
dc.contributor.authorGürsoy-Yüzügüllü, Özgeen_US
dc.contributor.authorCingöz, Burcuen_US
dc.contributor.authorAkçalı, Kamil Canen_US
dc.contributor.authorÖztürk, Mehmeten_US
dc.date.accessioned2016-02-08T09:57:15Zen_US
dc.date.available2016-02-08T09:57:15Zen_US
dc.date.issued2010en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.departmentGenetics and Biotechnology Research Center (BİLGEN)en_US
dc.description.abstractSenescence induction could be used as an effective treatment for hepatocellular carcinoma (HCC). However, major senescence inducers (p53 and p16Ink4a) are frequently inactivated in these cancers.We tested whether transforming growth factor-β (TGF-β) could serve as a potential senescence inducer in HCC. First, we screened for HCC cell lines with intact TGF-β signaling that leads to small mothers against decapentaplegic (Smad)-targeted gene activation. Five cell lines met this condition, and all of them displayed a strong senescence response to TGF-β1 (1-5 ng/mL) treatment. Upon treatment, c-myc was down-regulated, p21Cip1 and p15Ink4b were up-regulated, and cells were arrested at G1. The expression of p16Ink4a was not induced, and the senescence response was independent of p53 status. A short exposure of less than 1 minute was sufficient for a robust senescence response. Forced expression of p21 Cip1 and p15Ink4b recapitulated TGF-β1 effects. Senescence response was associated with reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) induction and intracellular reactive oxygen species (ROS) accumulation. The treatment of cells with the ROS scavenger N-acetyl-L-cysteine, or silencing of the NOX4 gene, rescued p21Cip1 and p15Ink4b accumulation as well as the growth arrest in response to TGF-β. Human HCC tumors raised in immunodeficient mice also displayed TGF-β1-induced senescence. More importantly, peritumoral injection of TGF-β1 (2 ng) at 4-day intervals reduced tumor growth by more than 75%. In contrast, the deletion of TGF-β receptor 2 abolished in vitro senescence response and greatly accelerated in vivo tumor growth. Conclusion: TGF-β induces p53-independent and p16Ink4a-independent, but Nox4-dependent, p21Cip1-dependent, p15Ink4b-dependent, and ROS-dependent senescence arrest in well-differentiated HCC cells. Moreover, TGF-β-induced senescence in vivo is associated with a strong antitumor response against HCC.en_US
dc.identifier.doi10.1002/hep.23769en_US
dc.identifier.issn0270-9139en_US
dc.identifier.urihttp://hdl.handle.net/11693/22229en_US
dc.language.isoEnglishen_US
dc.publisherAmerican Association for the Study of Liver Diseaseen_US
dc.relation.isversionofhttp://dx.doi.org/10.1002/hep.23769en_US
dc.source.titleHepatologyen_US
dc.subjectAcetylcysteineen_US
dc.subjectCyclin dependent kinase inhibitor 1en_US
dc.subjectCyclin dependent kinase inhibitor 2Ben_US
dc.subjectDecapentaplegic proteinen_US
dc.subjectMyc proteinen_US
dc.subjectProtein p53en_US
dc.subjectReactive oxygen metaboliteen_US
dc.subjectReduced nicotinamide adenine dinucleotide phosphate oxidase 4en_US
dc.subjectSmad proteinen_US
dc.subjectTransforming growth factor betaen_US
dc.titleTransforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growthen_US
dc.typeArticleen_US
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Department of Molecular Biology and Genetics
Genetics and Biotechnology Research Center (BİLGEN)