3, 3'5 Triiodo L thyronine induces apoptosis in human breast cancer MCF-7 cells, repressing SMP30 expression through negative thyroid response elements.
3, 3'5 Triiodo L thyronine induces apoptosis in human breast cancer MCF-7 cells, repressing SMP30 expression through negative thyroid response elements.
复制标题
DOI：
10.1371/journal.pone.0020861
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mishra SK
中科院分区：
文献类型：
--
作者：
Sar P;Peter R;Rath B;Das Mohapatra A;Mishra SK
甲状腺激素调节细胞增殖、分化以及凋亡。然而，作为甲状腺激素信号转导的结果的细胞凋亡的分子机制知之甚少。衰老标志蛋白30（SMP30）的抗凋亡作用已在多种刺激反应和敲除模型中得到表征。我们早期的数据表明，甲状腺激素3，3 ′ 5三碘甲腺原氨酸（T3），抑制大鼠肝脏中的SMP 30。在高转移性MCF-7中，人乳腺癌细胞系T3处理抑制SMP30表达，导致细胞凋亡增强。流式细胞术和其他技术分析显示，SMP30在MCF-7中的过表达和沉默分别导致细胞凋亡的减速和加速。为了确定参与这种调节的顺式作用元件，我们分析了瞬时转染的hSMP 30启动子缺失报告载体在MCF-7细胞中的激素反应性。与预期的表观遗传结果相反，甲状腺激素下调hSMP30启动子活性，尽管甲状腺应答元件（TREs）上乙酰化H3的募集增强。从已建立的表观遗传学概念的角度来看，我们将这两个TREs归类为负反应元件。我们尝试siRNA介导TR β沉默，降低了SMP30基因表达的抑制倍数。在甲状腺激素存在下，组蛋白脱乙酰酶（HDAC）抑制剂曲古抑菌素-A（TSA）进一步抑制SMP 30启动子活性。上述发现支持将甲状腺反应元件归类为阴性反应元件，因为TSA通常应该逆转抑制。这是第一份关于甲状腺激素显著下调SMP30基因表达，进而诱导MCF-7人乳腺癌细胞凋亡的新机制见解的报告。我们相信，我们的研究为未来努力开发新的治疗方法以挑战乳腺癌的进展奠定了良好的基础。
Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3′5 Triiodo L Thyronine (T3), represses SMP30 in rat liver. In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis–acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRβ, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions. This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer.
登录
查看更多内容
影响因子：
7.3
作者：
Chimenti, Franco;Bizzarri, Bruna;Filetici, Patrizia
通讯作者：
Filetici, Patrizia
影响因子：
4.8
作者：
Alonso, Manuela;Goodwin, Charles;Weiss, Roy E.
通讯作者：
Weiss, Roy E.
DOI：
10.1006/bbrc.1998.9327
发表时间：
1998-09-18
影响因子：
3.1
作者：
Fujita, T;Inoue, H;Maruyama, N
通讯作者：
Maruyama, N
影响因子：
11.2
作者：
Elsheikh, Somaia E.;Green, Andrew R.;Ellis, Ian O.
通讯作者：
Ellis, Ian O.
影响因子：
6.6
作者：
Hara, M;Suzuki, S;Hashizume, K
通讯作者：
Hashizume, K