Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line
| Autor: | Satoru Kyo, Seiji Mabuchi, Jun Kawagoe, Chika Ohshima, Hirohisa Kurachi, Maki Saitoh, Masahide Ohmichi, Masaki Inoue, Kazuhiro Takahashi, Akiko Kimura, Hideki Igarashi, Toshifumi Takahashi, Tsuyoshi Ohta, Akiko Mori-Abe, Botao Du |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Telomerase
Time Factors Morpholines Breast Neoplasms medicine.disease_cause Models Biological Biochemistry Phosphatidylinositol 3-Kinases Genes Reporter Cell Line Tumor medicine Humans Raloxifene Telomerase reverse transcriptase Enzyme Inhibitors Phosphorylation Luciferases Promoter Regions Genetic neoplasms Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Nucleus Reverse Transcriptase Polymerase Chain Reaction Chemistry Raloxifene Hydrochloride Estrogen Antagonists NF-kappa B Estrogens Cell Biology Molecular biology Up-Regulation DNA-Binding Proteins enzymes and coenzymes (carbohydrates) Microscopy Fluorescence Chromones embryonic structures Carcinogenesis Protein Processing Post-Translational Cell Division Plasmids Protein Binding medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 278:43363-43372 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m304363200 |
| Popis: | The mechanism by which raloxifene acts in the chemoprevention of breast cancer remains unclear. Because telomerase activity is involved in estrogen-induced carcinogenesis, we examined the effect of raloxifene on estrogen-induced up-regulation of telomerase activity in MCF-7 human breast cancer cell line. Raloxifene inhibited the induction of cell growth and telomerase activity by 17beta-estradiol (E2). Raloxifene inhibited the E2-induced expression of the human telomerase catalytic subunit (hTERT), and transient expression assays using luciferase reporter plasmids containing various fragments of the hTERT promoter showed that the estrogen-responsive element appeared to be partially responsible for the action of raloxifene. E2 induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, attenuated the E2-induced increases of the telomerase activity and hTERT promoter activity. Raloxifene inhibited the E2-induced Akt phosphorylation. In addition, raloxifene also inhibited the E2-induced hTERT expression via the PI3K/Akt/NFkappaB cascade. Moreover, raloxifene also inhibited the E2-induced phosphorylation of hTERT, association of NFkappaB with hTERT, and nuclear accumulation of hTERT. These results show that raloxifene inhibited the E2-induced up-regulation of telomerase activity not only by transcriptional regulation of hTERT via an estrogen-responsive element-dependent mechanism and the PI3K/Akt/NFkappaB cascade but also by post-translational regulation via phosphorylation of hTERT and association with NFkappaB. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|