XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer.
XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer.
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DOI：
10.1158/1535-7163.mct-13-0416
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发表时间：
2014-03
影响因子：
5.7
通讯作者：
Altura RA
中科院分区：
文献类型：
--
作者：
Cheng Y;Holloway MP;Nguyen K;McCauley D;Landesman Y;Kauffman MG;Shacham S;Altura RA
抑制XPO 1（CRM 1）介导的多个肿瘤抑制蛋白的核输出已被提出作为一种新的癌症治疗策略，以关闭致癌信号和增强肿瘤抑制。Survivin是一种多功能蛋白质，当在细胞质中表达时具有致癌特性，其需要XPO 1-RanGTP复合物用于其核输出。我们在雌激素受体阳性和三阴性乳腺癌（TNBC）细胞系和人乳腺肿瘤异种移植模型中研究了药物样选择性核输出抑制剂（SINE）XPO 1拮抗剂KPT-185、KPT-251、KPT-276和KPT-330的抗肿瘤机制。KPT化合物显着抑制乳腺癌细胞的生长和诱导肿瘤细胞死亡，在体外和体内。这些药物最初促进存活素在肿瘤细胞核内的积累。然而，它们的主要体外作用是降低存活素细胞质蛋白水平，与细胞凋亡的发生相关。XPO 1抑制通过抑制CBP介导的STAT 3乙酰化和阻断STAT 3与Survivin启动子结合来抑制Survivin转录。此外，半胱天冬酶-3被激活以切割存活素，使其无法结合XIAP并阻断半胱天冬酶级联反应。总的来说，这些数据表明，通过SINE化合物抑制XPO 1抑制STAT 3反式激活，以阻断生存素的选择性致癌特性，并支持其在三阴性乳腺肿瘤中的临床应用。
Inhibition of XPO1 (CRM1)-mediated nuclear export of multiple tumor suppressor proteins has been proposed as a novel cancer therapeutic strategy to turn off oncogenic signals and enhance tumor suppression. Survivin is a multifunctional protein with oncogenic properties when expressed in the cytoplasm that requires the XPO1-RanGTP complex for its nuclear export. We investigated the anti-tumor mechanisms of the drug-like selective inhibitors of nuclear export (SINE) XPO1 antagonists, KPT-185, KPT-251 KPT-276, and KPT-330 in estrogen-receptor positive and triple negative breast cancer (TNBC) cell lines and xenograft models of human breast tumors. KPT compounds significantly inhibited breast cancer cell growth and induced tumor cell death, both in vitro and in vivo. These drugs initially promoted survivin accumulation within tumor cell nuclei. However, their major in vitro effect was to decrease survivin cytoplasmic protein levels, correlating with the onset of apoptosis. XPO1 inhibition repressed Survivin transcription by inhibiting CBP-mediated STAT3 acetylation, and blocking STAT3 binding to the Survivin promoter. Additionally, caspase-3 was activated to cleave survivin, rendering it unavailable to bind XIAP and block the caspase cascade. Collectively, these data demonstrate that XPO1 inhibition by SINE compounds represses STAT3 transactivation to block the selective oncogenic properties of survivin and supports their clinical use in triple negative breast tumors.