title: 17Alpha-estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells.
abstract: A pharmacological dose (2.5-10 microM) of 17alpha-estradiol (17alpha-E(2)) exerted a cytotoxic effect on human leukemias Jurkat T and U937 cells, which was not suppressed by the estrogen receptor (ER) antagonist ICI 182,780. Along with cytotoxicity in Jurkat T cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, PARP degradation, and DNA fragmentation were induced. The cytotoxicity of 17alpha-E(2) was not blocked by the anti-Fas neutralizing antibody ZB-4. While undergoing apoptosis, there was a remarkable accumulation of G(2)/M cells with the upregulatoin of cdc2 kinase activity, which was reflected in the Thr56 phosphorylation of Bcl-2. Dephosphorylation at Tyr15 and phosphorylation at Thr161 of cdc2, and significant increase in the cyclin B1 level were underlying factors for the cdc2 kinase activation. Whereas the 17alpha-E(2)-induced apoptosis was completely abrogated by overexpression of Bcl-2 or by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G(2)/M cells significantly increased. The caspase-8 inhibitor z-IETD-fmk failed to influence 17alpha-E(2)-mediated caspase-9 activation, but it markedly reduced caspase-3 activation and PARP degradation with the suppression of apoptosis, indicating the contribution of caspase-8; not as an upstream event of the mitochondrial cytochrome c release, but to caspase-3 activation. In the presence of hydroxyurea, which blocked the cell cycle progression at the G(1)/S boundary, 17alpha-E(2) failed to induce the G(2)/M arrest as well as apoptosis. These results demonstrate that the cytotoxicity of 17alpha-E(2) toward Jurkat T cells is attributable to apoptosis mainly induced in G(2)/M-arrested cells, in an ER-independent manner, via a mitochondria-dependent caspase pathway regulated by Bcl-2.
authors.affiliation: Laboratory of Immunobiology, Department of Microbiology, School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, South Korea.
authors.forename: Do Youn
authors.initials: DY
authors.lastname: Jun
authors.forename: Hae Sun
authors.initials: HS
authors.lastname: Park
authors.forename: Jun Seok
authors.initials: JS
authors.lastname: Kim
authors.forename: Jong Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Wan
authors.initials: W
authors.lastname: Park
authors.forename: Bang Ho
authors.initials: BH
authors.lastname: Song
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Dennis
authors.initials: D
authors.lastname: Taub
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000627:therapeutic use / Q000633:toxicity*; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D004958:Estradiol; D020169:Caspases