Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line.
In: Journal of Biological Chemistry, Jg. 278 (2003-10-31), Heft 44, S. 43363-43372
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Zugriff:
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 17β-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 E2induced hTERT expression via the PI3K/Akt/NFκB cascade. Moreover, raloxifene also inhibited the E2induced phosphorylation of hTERT, association of NFκB with hTERT, and nuclear accumulation of hTERT. These results show that raloxifene inhibited the E2induced up-regulation of telomerase activity not only by transcriptional regulation of hTERT via an estrogenresponsive element-dependent mechanism and the PI3K/Akt/NFκB cascade but also by post-translational regulation via phosphorylation of hTERT and association with NFκB. [ABSTRACT FROM AUTHOR]
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Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line.
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Autor/in / Beteiligte Person: | Kawagoe, Jun ; Ohmichi, Masahide ; Takahashi, Toshifumi ; Ohshima, Chika ; Mabuchi, Seiji ; Takahashi, Kazuhiro ; Igarashi, Hideki ; Mori-Abe, Akiko ; Saitoh, Maki ; Du, Botao ; Ohta, Tsuyoshi ; Kimura, Akiko ; Kyo, Satoru ; Inoue, Masaki ; Kurachi, Hirohisa |
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Zeitschrift: | Journal of Biological Chemistry, Jg. 278 (2003-10-31), Heft 44, S. 43363-43372 |
Veröffentlichung: | 2003 |
Medientyp: | academicJournal |
ISSN: | 0021-9258 (print) |
DOI: | 10.1074/jbc.M304363200 |
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