title: Roscovitine, a selective CDK inhibitor, reduces the basal and estrogen-induced phosphorylation of ER-α in human ER-positive breast cancer cells.
abstract: Roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, arrests human estrogen receptor-α (ER-α) positive MCF-7 breast cancer cells in the G(2) phase of the cell cycle and concomitantly induces apoptosis via a p53-dependent pathway. The effect of ROSC is markedly diminished in MCF-7 cells maintained in the presence of estrogen-mimicking compounds. Therefore, we decided to examine whether ROSC has any effect on the functional status of the ER-α transcription factor. Exposure of MCF-7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 in a concentration and time-dependent manner. This inhibition of site-specific modification of CDK7 at Ser164/170 prevented phosphorylation of RNA polymerase II and reduced basal phosphorylation of ER-α at Ser118 in non-stimulated MCF-7 cells (resulting in its down-regulation). In MCF-7 cells, estrogen induced strong phosphorylation of ER-α at Ser118 but not at Ser104/Ser106. ROSC prevented this estrogen-promoted activating modification of ER-α. Furthermore, we sought to determine whether the activity of ROSC could be enhanced by combining it with an anti-estrogen. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), affected breast cancer cell lines irrespective of their ER status. In combination with ROSC, however, it had a different impact, enhancing G(1) or G(2) arrest. Our results indicate that ROSC prevents the activating phosphorylation of ER-α and that its mode of action is strongly dependent on the cellular context. Furthermore, our data show that ROSC can be combined with anti-estrogen therapy. The inhibitory effect of TAM on ER-negative cancer cells indicates that SERMs crosstalk with other steroid hormone receptors.
authors.affiliation: Cell Cycle Regulation Group, Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. jozefa.gadek-wesierski@meduniwien.ac.at
authors.forename: Józefa
authors.initials: J
authors.lastname: Węsierska-Gądek
authors.forename: David
authors.initials: D
authors.lastname: Gritsch
authors.forename: Nora
authors.initials: N
authors.lastname: Zulehner
authors.forename: Oxana
authors.initials: O
authors.lastname: Komina
authors.forename: Margarita
authors.initials: M
authors.lastname: Maurer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism; D000077546:Roscovitine; D013629:Tamoxifen / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011687:Purines; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D000077546:Roscovitine; D004958:Estradiol; D004004:Dichlororibofuranosylbenzimidazole; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II