Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells

被引:34
|
作者
Kallio, Anu [2 ,3 ]
Guo, Tao [2 ,4 ,5 ]
Lamminen, Elisa [2 ]
Seppanen, Jani [2 ]
Kangas, Lauri [6 ]
Vaananen, H. Kalervo [2 ]
Harkonen, Pirkko [1 ]
机构
[1] Lund Univ, MAS Univ Hosp, Dept Lab Med, S-20502 Malmo, Sweden
[2] Univ Turku, Inst Biomed, Dept Anat, FIN-20520 Turku, Finland
[3] Turku Grad Sch Biomed Sci, Turku, Finland
[4] Huazhong Univ Sci & Technol, Union Hosp, Inst Hematol, Wuhan 430022, Hubei, Peoples R China
[5] Lab Biotargeted Therapy Hubei Prov, Wuhan 430022, Hubei, Peoples R China
[6] Hormos Med Ltd, Turku, Finland
基金
芬兰科学院;
关键词
osteoblast; U2OS; estradiol; estrogen receptor; OPG; IL-6;
D O I
10.1016/j.mce.2008.03.005
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
In the current work, we compared the ability of 17 beta-estradiol (E-2) and the selective estrogen receptor modulators (SERMs), tamoxifen (Tam), raloxifene (Ral) and ospemifene (Osp) to promote the survival of osteoblast-derived cells against etoposide-incluced apoptosis. In order to compare the roles of the two estrogen receptor (ER) isotypes, we created a U2OS human osteosarcoma cell line stably expressing either ERalpha (ER alpha) or ERbeta (ER beta). Transfection with either of the ERs was able to render the U2OS cells sensitive to E-2. We show that E2 opposed etoposide-induced apoptosis and that the effect was mediated via both ER isotypes. The ER isotype selective agonists propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPN) had the same effect in U2OS/ER alpha and U20S/ER beta cells, respectively. Osp also opposed apoptosis at least in U2OS/ERa cells. Tam and Ral were not able to protect against etoposide-induced cell death. In order to evaluate the protective effects of E-2 and Osp upon etoposide challenge, we studied the expression of two E-2-regulated, osteoblast-produced cytokines, IL-6 and OPG in E-2 and SERM-treated U2OS/ER alpha and U2OS/ER beta cells. Etoposide strongly increased expression of IL-6 and decreased that of OPG. E-2 opposed IL-6 increase only in U2OS/ER alpha cells and OPG decrease primarily in ER beta cells. Osp opposed the effect of etoposide on OPG primarily in U2OS/ER beta cells but interestingly, it had little effect on IL-6 expression. E2, PPT, DNP and Osp also inhibited etoposide-induced death and cytokine changes in SAOS-2 osteosarcoma cells expressing endogenous ER alpha and ER beta. Collectively, our results suggest that the osteoblast protective anti-apoptotic effects of E-2 are mediated by both ER alpha and ER beta but those of Osp primarily by ER alpha. In addition, E-2 and Osp opposed the etoposide-induced increase of IL-6 and decrease of OPG which changes would increase osteoclastic activity. These anti-resorptive effects of E-2 and Osp upon etoposide challenge differed from each other and they seemed to be differentially mediated in ER(x and ER beta expressing osteoblast-derived U2OS cells. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:38 / 48
页数:11
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