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 17␤-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/NFB cascade. Moreover, raloxifene also inhibited the E2-induced phosphorylation of hTERT, association of NFB 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 estrogenresponsive element-dependent mechanism and the PI3K/Akt/NFB cascade but also by post-translational regulation via phosphorylation of hTERT and association with NFB.

Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines

“…hTERT-expressing cells were evaluated for cytoplasmic (C), nuclear-cytoplasmic (N þ C), and nuclear (N) fluorescence (Figure 9a). E 2 induced nuclear accumulation of hTERT from 30 min to 24 h in Caov-3 cells (Figure 9b), as we have also demonstrated in MCF-7 cells (Kawagoe et al, 2003). Most of the TERT protein was also localized in the cytoplasm under normal serum conditions (data not shown).…”

“…Most of the TERT protein was also localized in the cytoplasm under normal serum conditions (data not shown). Pretreatment with LY294002, ICI 182,780, or BAY11-7082 attenuated the E 2 -induced nuclear accumulation of hTERT in both Caov-3 (Figure 9c, left panel) and MCF-7 (Figure 9c, right panel) (Kawagoe et al, 2003) cells. These data suggest that E 2 -induced nuclear accumulation of hTERT is mediated by ER via a PI3K/Akt/NFkB cascade in both Caov-3 and MCF-7 cells.…”

Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis

“…Further investigation indicates that NF-kB is necessary for human Tlymphotropic virus type 1 (HTLV-1) oncoprotein Tax induced telomerase expression during transmission of HTLV-1 to primary T cells (Sinha-Datta et al, 2004). In addition, NF-kB is reported to mediate estrogeninduced telomerase expression in MCF-7 human breast cancer cells (Kawagoe et al, 2003). These reports suggest that both c-IAP2 and telomerase promoters might be controlled by NF-kB.…”

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

“…In this sense, our results suggest that PZsc may have a stronger ability to promote PCa progression. Several groups have reported that sex hormones can regulate hTERT expression, [54][55][56] but the mechanism is unknown. We also found that E2 increased hTERT mRNA expression.…”