Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness.
Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness.
复制标题
葡萄糖调节的蛋白78控制凋亡和自噬之间的串扰，以确定抗雌激素反应性。
DOI：
10.1158/0008-5472.can-12-0269
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Clarke R
中科院分区：
文献类型：
--
作者：
Cook KL;Shajahan AN;Wärri A;Jin L;Hilakivi-Clarke LA;Clarke R
虽然超过 70% 的乳腺癌表达雌激素受体-α (ER+)，但针对这些受体的内分泌治疗常常失败。治疗耐药性的分子机制仍不清楚。我们研究了葡萄糖调节蛋白 78 (GRP78) 在介导雌激素抵抗中的潜在作用。与正常乳腺组织相比，人类乳腺肿瘤显示 GRP78 表达增加。然而，与 HER2 扩增或三阴性乳腺肿瘤相比，ER+ 乳腺肿瘤中的 GRP78 表达降低。 ER+ 抗雌激素耐药细胞和具有获得性抗雌激素耐药表型的 ER+ 肿瘤均显示出过表达 GRP78，而在从头耐药的情况下未观察到这种现象。 GRP78 的敲低恢复了耐药细胞的抗雌激素敏感性，而 GRP78 的过度表达则促进了敏感细胞的耐药性。从机制上讲，GRP78 整合了多种细胞信号通路来抑制细胞凋亡并刺激促存活自噬，这依赖于 TSC2/AMPK 介导的 mTOR 抑制，但不依赖于 beclin-1。抑制自噬可防止 GRP78 介导的内分泌抵抗，而抑制 caspase 则可消除因 GRP78 丢失而导致的重新敏化。同时敲低 GRP78 和 beclin-1 可协同恢复耐药细胞的抗雌激素敏感性。总之，我们的研究结果揭示了 GRP78 在细胞信号通路整合中的新作用，包括未折叠蛋白反应、细胞凋亡和自噬，以确定细胞命运以响应抗雌激素治疗。
While more than 70% of breast cancers express estrogen receptor-α (ER+), endocrine therapies targeting these receptors often fail. The molecular mechanisms that underlie treatment resistance remain unclear. We investigated the potential role of glucose-regulated protein 78 (GRP78) in mediating estrogen resistance. Human breast tumors showed increased GRP78 expression when compared with normal breast tissues. However, GRP78 expression was reduced in ER+ breast tumors compared with HER2-amplifed or triple-negative breast tumors. ER+ antiestrogen-resistant cells and ER+ tumors with an acquired resistant antiestrogen phenotype were both shown to overexpress GRP78, which was not observed in cases of de novo resistance. Knockdown of GRP78 restored antiestrogen sensitivity in resistant cells, and overexpression of GRP78 promoted resistance in sensitive cells. Mechanistically, GRP78 integrated multiple cellular signaling pathways to inhibit apoptosis and stimulate prosurvival autophagy, which was dependent on TSC2/AMPK-mediated mTOR inhibition but not on beclin-1. Inhibition of autophagy prevented GRP78-mediated endocrine resistance, whereas caspase inhibition abrogated the resensitization that resulted from GRP78 loss. Simultaneous knockdown of GRP78 and beclin-1 synergistically restored antiestrogen sensitivity in resistant cells. Together, our findings reveal a novel role for GRP78 in the integration of cellular signaling pathways including the unfolded protein response, apoptosis, and autophagy to determine cell fate in response to antiestrogen therapy.