The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis
The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis
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DOI：
10.1073/pnas.0307337101
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发表时间：
2004-02-24
影响因子：
11.1
通讯作者：
Shioda, T
中科院分区：
文献类型：
--
作者：
Hur, JY;Chesnes, J;Shioda, T
越来越多的证据表明，一些雌激素依赖的人类乳腺癌不仅需要雌激素的增殖，而且生存。为了深入了解雌激素饥饿或抗雌激素暴露的乳腺癌细胞凋亡的分子机制，我们表征了MCF-7/BUS人乳腺癌细胞基因表达谱的变化，并揭示了Bilk的强烈诱导，Bilk是仅BH 3促凋亡蛋白的成员。雌激素饥饿或暴露于氟维司群强烈诱导Bilk mRNA转录物和蛋白质，氟维司群是一种纯抗雌激素，与天然雌激素竞争结合雌激素受体。这种Bik诱导先于凋亡性细胞死亡，其被泛半胱天冬酶抑制剂zVAD-favor阻断。在存在或不存在雌激素或抗雌激素的情况下，Bcl-2、Bcl-X-L或Bax等Bcl-2相关蛋白的含量仅显示出微小的变化。通过使用小干扰RNA抑制Bilk表达，有效地阻断了氟维司群诱导的乳腺癌细胞凋亡。这些结果表明，Bik在MCF-7/BUS细胞中是在雌激素信号不存在的情况下被诱导的，并且在抗雌激素引起的乳腺癌细胞凋亡中起关键作用。
Evidence has been accumulating that some estrogen-dependent human breast cancers require estrogen for not only proliferation but also survival. To obtain insights into the molecular mechanisms of apoptosis of breast cancer cells subjected to estrogen starvation or exposed to antiestrogens, we characterized changes in the gene expression profile of MCF-7/BUS human breast cancer cells and revealed a strong induction of Bilk, a member of the BH3-only proapoptotic proteins. The Bilk mRNA transcript and protein were strongly induced by estrogen starvation or exposure to fulvestrant, a pure antiestrogen that competes with the natural estrogens for binding to the estrogen receptors. This Bik induction preceded apoptotic cell death, which was blocked by zVAD-fmk, a pan-caspase inhibitor. Amounts of the Bcl-2-related proteins, such as Bcl-2, Bcl-X-L, or Bax, showed only marginal changes in the presence or absence of estrogens or antiestrogens. Suppression of Bilk expression by using the small interfering RNA effectively blocked the fulvestrant-induced breast cancer cell apoptosis. These results indicate that Bik is induced in MCF-7/BUS cells in the absence of estrogen signaling and plays a critical role in the antiestrogen-provoked breast cancer cell apoptosis.