title: A molecular understanding of D-homoestrone-induced G2/M cell cycle arrest in HeLa human cervical carcinoma cells.
abstract: 2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested D-ring-modified analogue of estrone, D-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by D-homoestrone in HeLa cells. Apoptosis triggered by D-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that D-homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin-dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, D-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the D-homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds.
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
authors.forename: Renáta
authors.initials: R
authors.lastname: Minorics
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
authors.forename: Noémi
authors.initials: N
authors.lastname: Bózsity
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Molnár
authors.affiliation: Department of Organic Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.affiliation: Department of Organic Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Mernyák
authors.affiliation: Department of Organic Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Biochemistry, University of Szeged, Szeged, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszki
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000473:pathology*
chemical_list: D019926:Cyclin B; D012333:RNA, Messenger; D014404:Tubulin; D004970:Estrone; C012349:D-homoestrone; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D053181:Caspase 8; D053453:Caspase 9
keywords: Cdc25B and C; G2/M phase transition; HeLa cells; cell cycle arrest; d-homoestrone; intrinsic apoptotic pathway; loss of function of Cdk1; stathmin; tubulin polymerization