Estrogen receptor a inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression
Estrogen receptor a inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression
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DOI：
10.1073/pnas.1403685112
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发表时间：
2015-04-14
影响因子：
11.1
通讯作者：
Shapiro, David J.
中科院分区：
文献类型：
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作者：
Andruska, Neal D.;Zheng, Xiaobin;Shapiro, David J.
复发性雌激素受体α（ER α）阳性的乳腺癌和卵巢癌通常是治疗抵抗性的。通过筛选和功能验证，我们确定了BHPI，一种有效的非竞争性小分子ER α生物调节剂，可选择性阻断耐药ER α阳性乳腺癌和卵巢癌细胞的增殖。在乳腺癌的小鼠异种移植模型中，BHPI诱导了快速和实质性的肿瘤消退。尽管BHPI有效地抑制核雌激素-ER α调节的基因表达，但BHPI是有效的，因为它增强了内质网（EnR）应激传感器的持续ER α依赖性激活、未折叠蛋白质反应（UPR）和蛋白质合成的持续抑制。BHPI扭曲了一个新描述的雌激素-ER α的作用：轻度和短暂的UPR激活。相反，BHPI激发大量和持续的UPR激活，将UPR从保护性转化为毒性。在ER α +癌细胞中，BHPI快速超活化质膜PLC。产生肌醇1，4，5-三磷酸（IP 3），其打开EnR IP 3R钙通道，迅速耗尽EnR Ca 2+储存。这导致普遍定期审议的所有三个分支都启动。PERK臂的激活刺激真核起始因子2 α（eIF 2 α）的磷酸化，导致蛋白质合成的快速抑制。细胞试图恢复EnR Ca 2+水平，但开放的EnR IP 3R钙通道导致ATP消耗无效循环，导致能量传感器AMP激活的蛋白激酶激活和真核细胞延伸因子2（eEF 2）的磷酸化。eEF 2磷酸化抑制第二位点的蛋白质合成。BHPI的新的作用模式，高效力，和治疗耐药肿瘤细胞的有效性，使其成为进一步的机制和治疗探索的特殊候选人。
Recurrent estrogen receptor a (ER alpha)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ER alpha biomodulator that selectively blocks proliferation of drug-resistant ERa-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ER alpha-regulated gene expression, BHPI is effective because it elicits sustained ERa-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ER alpha: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ER alpha+ cancer cells, BHPI rapidly hyperactivates plasma membrane PLC., generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca2+ levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapyresistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.