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M304363200v1
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Papers In Press, published online ahead of print August 13, 2003
J. Biol. Chem, 10.1074/jbc.M304363200
Submitted on April 25, 2003
Revised on August 12, 2003
Accepted on August 13, 2003

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

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, and Hirohisa Kurachi

Department of Obstetrics and Gynecology, Yamagata University, Yamagata, Yamagata 990-9585

Corresponding Author: masa{at}med.id.yamagata-u.ac.jp

The mechanism by which raloxifene acts in chemoprevention of breast cancer remains unclear. Since 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 17b-estradiol (E2). Raloxifene inhibited the E2-induced expression of 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 (ERE) 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/NFkB cascade. Moreover, raloxifene also inhibited the E2-induced phosphorylation of hTERT, association of NFkB 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 ERE-dependent mechanism and the PI3K/Akt/NFkB cascade, but also by post-translational regulation via phosphorylation of hTERT and association with NFkB.


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