Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells
Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells
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DOI：
10.1158/1078-0432.ccr-05-2051
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发表时间：
2006-06-01
影响因子：
11.5
通讯作者：
Weinstein, I. Bernard
中科院分区：
文献类型：
--
作者：
Lim, Jin T. E.;Joe, Andrew K.;Weinstein, I. Bernard
在先前的研究中，我们发现舒林酸硫化物和依昔舒林（舒林酸砜，Aptosyn）导致生长抑制，将细胞阻滞在细胞周期的G期，并诱导人乳腺癌细胞系的凋亡。这些作用与细胞周期蛋白D1表达减少有关。本研究的重点是舒林酸硫化物和exisulind对乳腺癌细胞激素信号成分的影响。我们发现雌激素受体（ER）阳性和孕激素受体（PR）阳性T47 D乳腺癌细胞对舒林酸硫化物或依昔舒林的生长抑制作用比ER阴性PR阴性MB-MDA-468乳腺癌细胞更敏感。进一步的研究表明，舒林酸硫化物和依昔舒林引起T47 D细胞中ER和PR-A和PR-B的表达显著下调。然而，这两种化合物都没有引起T47 D细胞中视黄酸受体α（RAR α）、RAR β或RAR α表达的重大变化。舒林酸硫化物和依昔舒林也引起雌激素反应性MCF-7乳腺癌细胞中ER表达的降低。这两种化合物也显着抑制雌激素刺激激活的雌激素反应启动子在瞬时转染报告基因测定。用特异性蛋白激酶G（PKG）激活剂处理T47 D细胞不会导致ER或PR表达的降低。因此，尽管舒林酸硫化物和依昔舒林可引起PKG的激活，但这两种化合物对ER和PR表达的抑制作用似乎不是由PKG介导的。我们的研究结果表明，舒林酸硫化物和exisulind在ER阳性和PR阳性的人乳腺癌细胞的生长抑制可能是介导的，部分，通过抑制ER和PR信号。因此，这些化合物和相关化合物可提供预防和治疗人类乳腺癌，特别是ER阳性的乳腺癌的新方法。
In previous studies, we found that sulindac sulfide and exisulind (sulindac sulfone, Aptosyn) cause growth inhibition, arrest cells in the G, phase of the cell cycle, and induce apoptosis in human breast cancer cell lines. These effects were associated with decreased expression of cyclin D1. The present study focuses on the effects of sulindac sulfide and exisulind on hormone signaling components in breast cancer cells. We found that estrogen receptor (ER)- positive and progesterone receptor (PR) - positive T47D breast cancer cells were somewhat more sensitive to growth inhibition by sulindac sulfide or exisulind than ER-negative PR-negative MB-MDA-468 breast cancer cells. Further studies indicated that sulindac sulfide and exisulind caused marked down-regulation of expression of the ER and PR-A and PR-B in T47D cells. However, neither compound caused a major change in expression of the retinoic acid receptor alpha (RAR alpha), RAR beta, or RAR alpha in T47D cells. Sulindac sulfide and exisulind also caused a decrease in expression of the ER in estrogen-responsive MCF-7 breast cancer cells. Both compounds also markedly inhibited estrogen-stimulated activation of an estrogen-responsive promoter in transient transfection reporter assays. Treatment of T47D cells with specific protein kinase G (PKG) activators did not cause a decrease in ER or PR expression. Therefore, although sulindac sulfide and exisulind can cause activation of PKG, the inhibitory effects of these two compounds on ER and PR expression does not seem to be mediated by PKG. Our findings suggest that the growth inhibition by sulindac sulfide and exisulind in ER-positive and PR-positive human breast cancer cells may be mediated, in part, by inhibition of ER and PR signaling. Thus, these and related compounds may provide a novel approach to the prevention and treatment of human breast cancers, especially those that are ER positive.