GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis
GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis
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DOI：
10.1158/0008-5472.can-06-4594
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Lee, Amy S.
中科院分区：
文献类型：
--
作者：
Fu, Yong;Li, Jianze;Lee, Amy S.
阻断雌激素合成的激素疗法的最新发展代表了雌激素受体阳性乳腺癌治疗的重大进展。然而，癌细胞通常会获得适应性，从而产生耐药性。最近的一份报告显示，雌激素饥饿诱导的乳腺癌细胞凋亡需要BIK，一种主要位于内质网（ER）的凋亡BH 3蛋白。寻找在ER与BIK相互作用的新伙伴，我们发现BIK选择性地与葡萄糖调节蛋白GRP 78/BiP形成复合物，GRP 78/BiP是一种主要的ER伴侣，具有在肿瘤微环境中天然诱导的促生存特性。GRP 78过表达减少ER靶向BIK诱导的293 T细胞凋亡对于雌激素依赖性MCF-7/BUS乳腺癌细胞，GRP 78的过表达抑制了雌激素饥饿诱导的BAX激活、线粒体通透性转换和随后的凋亡。此外，通过小干扰RNA（siRNA）敲低内源性GRP 78使MCF-7/BUS细胞对雌激素饥饿诱导的凋亡敏感。当BIK的表达也被siRNA降低时，这种作用显著降低。我们的研究结果提供了第一个证据表明，GRP 78赋予抵抗雌激素饥饿诱导的人乳腺癌细胞凋亡，通过一种新的机制介导的BIK。这些结果进一步表明，肿瘤细胞中的GRP 78表达水平可以作为对基于雌激素饥饿的激素治疗的反应性的预后标志物，并且靶向GRP 78的联合治疗可以增强功效并降低抗性。
The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor-positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation-induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells' overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation-induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance.