Osteoprotegerin Production by Breast Cancer Cells Is Suppressed by Dexamethasone and Confers Resistance Against TRAIL-induced Apoptosis
Osteoprotegerin Production by Breast Cancer Cells Is Suppressed by Dexamethasone and Confers Resistance Against TRAIL-induced Apoptosis
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DOI：
10.1002/jcb.22232
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发表时间：
2009-09-01
影响因子：
4
通讯作者：
Hofbauer, Lorenz C.
中科院分区：
文献类型：
--
作者：
Rachner, Tilman D.;Benad, Peggy;Hofbauer, Lorenz C.
骨保护素（OPG）是核因子-κ B配体受体激活剂（RANKL）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）的诱饵受体。虽然RANKL是破骨细胞生成所必需的，并促进乳腺癌迁移到骨，TRAIL促进乳腺癌细胞凋亡。我们分析了OPG和TRAIL在雌激素受体阳性的MCF-7细胞和受体阴性的MDA-MB-231细胞中的表达及其调节。在这两种细胞中，OPG mRNA水平和蛋白质分泌量的剂量和时间依赖性增强白细胞介素（IL）-1 β和地塞米松抑制。与MCF-7细胞相比，MDA-MB-231大量表达TRAIL mRNA，IL-1 β可增强其表达，地塞米松可抑制其表达。TRAIL可激活caspase-3、caspase-7和多聚ADP核糖聚合酶，减少MDA-MB-231的细胞数，但对MCF-7细胞无影响。与非靶siRNA处理的MDA-MB-231细胞相比，针对OPG的基因沉默siRNA导致31%的高凋亡率。此外，与在缺乏OPG的新鲜培养基中暴露于TRAIL的细胞相比，在条件培养基（含有OPG）中培养的细胞中，TRAIL诱导的凋亡显著较少（P
Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-kappa B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor-positive MCF-7 cells and receptor-negative MDA-MB-231 cells. In both cells, OPG mRNA levels and protein secretion were dose- and time-dependently enhanced by interleukin (IL)-1 beta and suppressed by dexamethasone. In contrast to MCF-7 cells, MDA-MB-231 abundantly expressed TRAIL mRNA, which was enhanced by IL-1 beta and inhibited by dexamethasone. TRAIL activated pro-apoptotic caspase-3, -7, and poly-ADP-ribose polymerase and decreased cell numbers of MDA-MB-231, but had no effect on MCF-7 cells. Gene silencing siRNA directed against OPG resulted in a 31% higher apoptotic rate compared to non-target siRNA-treated MDA-MB-231 cells. Furthermore, TRAIL induced significantly less apoptosis in cells cultured in conditioned media (containing OPG) compared to cells exposed to TRAIL in fresh medium lacking OPG (P