Raloxifene inhibits estrogen-induced up-regulation of telomerase activity in a human breast cancer cell line.

Abstract

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.

• Authors: Jun Kawagoe, Masahide Ohmichi, Toshifumi Takahashi, Chika Ohshima, Seiji Mabuchi, Kazuhiro Takahashi, Hideki Igarashi, Akiko Mori-Abe, Maki Saitoh, Botao Du, Tsuyoshi Ohta, Akiko Kimura, Satoru Kyo, Masaki Inoue, Hirohisa Kurachi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 44 Pg. 43363-72 (Oct 31 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12917431 (Publication Type: Journal Article)

Chemical References

• Chromones
• DNA-Binding Proteins
• Enzyme Inhibitors
• Estrogen Antagonists
• Estrogens
• Morpholines
• NF-kappa B
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Raloxifene Hydrochloride
• Luciferases
• Phosphatidylinositol 3-Kinases
• Telomerase

Topics

• Breast Neoplasms (metabolism)
• Cell Division
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Chromones (pharmacology)
• DNA-Binding Proteins
• Enzyme Inhibitors (pharmacology)
• Estrogen Antagonists (pharmacology)
• Estrogens (metabolism)
• Genes, Reporter
• Humans
• Luciferases (metabolism)
• Microscopy, Fluorescence
• Models, Biological
• Morpholines (pharmacology)
• NF-kappa B (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Plasmids (metabolism)
• Promoter Regions, Genetic
• Protein Binding
• Protein Processing, Post-Translational
• Raloxifene Hydrochloride (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Telomerase (metabolism)
• Time Factors
• Up-Regulation