Bcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27(Kip1)-dependent G1/S cell cycle arrest in conjunction with NF-kappaB activation

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dc.contributor.authorBatsi, C.en
dc.contributor.authorMarkopoulou, S.en
dc.contributor.authorKontargiris, E.en
dc.contributor.authorCharalambous, C.en
dc.contributor.authorThomas, C.en
dc.contributor.authorChristoforidis, S.en
dc.contributor.authorKanavaros, P.en
dc.contributor.authorConstantinou, A. I.en
dc.contributor.authorMarcu, K. B.en
dc.contributor.authorKolettas, E.en
dc.date.accessioned2015-11-24T19:33:22Z
dc.date.available2015-11-24T19:33:22Z
dc.identifier.issn1873-2968-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/23528
dc.rightsDefault Licence-
dc.subjectApoptosis/*drug effectsen
dc.subjectCell Cycle/drug effects/geneticsen
dc.subjectCyclin-Dependent Kinase Inhibitor p21/geneticsen
dc.subjectCyclin-Dependent Kinase Inhibitor p27/geneticsen
dc.subjectCyclin-Dependent Kinases/antagonists & inhibitorsen
dc.subjectEstradiol/*analogs & derivatives/pharmacologyen
dc.subjectG1 Phase/drug effects/*physiologyen
dc.subjectHumansen
dc.subjectJurkat Cells/cytology/*drug effectsen
dc.subjectNF-kappa B/*physiologyen
dc.subjectProto-Oncogene Proteins c-bcl-2/*physiologyen
dc.subjectS Phase/drug effects/*physiologyen
dc.titleBcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27(Kip1)-dependent G1/S cell cycle arrest in conjunction with NF-kappaB activationen
heal.abstract2-Methoxyestradiol (2-ME2) induces leukemia cells to undergo apoptosis in association with Bcl-2 inactivation but the mechanisms whereby Bcl-2 contributes to protection against programmed cell death in this context remain unclear. Here we showed that 2-ME2 inhibited the proliferation of Jurkat leukemia cells by markedly suppressing the levels of cyclins D3 and E, E2F1 and p21(Cip1/Waf1) and up-regulating p16(INK4A). Further, 2-ME2 induced apoptosis of Jurkat cells in association with down-regulation and phosphorylation of Bcl-2 (as mediated by JNK), up-regulation of Bak, activation of caspases-9 and -3 and PARP-1 cleavage. To determine the importance and mechanistic role of Bcl-2 in this process, we enforced its expression in Jurkat cells by retroviral transduction. Enforcing Bcl-2 expression in Jurkat cells abolished 2-ME2-induced apoptosis and instead produced a G1/S phase cell cycle arrest in association with markedly increased levels of p27(Kip1). Bcl-2 and p27(Kip1) were localized mainly in the nucleus in these apoptotic resistant cells. Interestingly, NF-kappaB activity and p50 levels were increased by 2-ME2 and suppression of NF-kappaB signaling reduced p27(Kip1) expression and sensitized cells to 2-ME2-induced apoptosis. Importantly, knocking-down p27(Kip1) in Jurkat Bcl-2 cells sensitized them to spontaneous and 2-ME2-induced apoptosis. Thus, Bcl-2 prevented the 2-ME2-induced apoptotic response by orchestrating a p27(Kip1)-dependent G1/S phase arrest in conjunction with activating NF-kappaB. Thus, we achieved a much better understanding of the penetrance and mechanistic complexity of Bcl-2 dependent anti-apoptotic pathways in cancer cells and why Bcl-2 inactivation is so critical for the efficacy of apoptosis and anti-proliferative inducing drugs like 2-ME2.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1016/j.bcp.2009.03.017-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/19447221-
heal.identifier.secondaryhttp://ac.els-cdn.com/S0006295209001920/1-s2.0-S0006295209001920-main.pdf?_tid=dfc27659d323fd218c69e2c87b80e443&acdnat=1332999304_2a86e691afcf041d1042e826a0711e53-
heal.journalNameBiochem Pharmacolen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2009-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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