Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ.
Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ.
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DOI：
10.1038/s41388-018-0425-7
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发表时间：
2019-01
期刊：
影响因子：
8
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Liu Z;Wei Y;Zhang L;Yee PP;Johnson M;Zhang X;Gulley M;Atkinson JM;Trebak M;Wang HG;Li W
胶质母细胞瘤（GBM）是最具侵袭性的脑癌，没有有效的治疗方法。Hippo通路转录共激活因子雅普/TAZ被认为是GBM进展的驱动因子，可能是治疗靶点。在此，我们在对1650种化合物的无偏筛选中发现，GBM能够通过抑制雅普/TAZ活性来抑制GBM细胞的存活。与其作为L-型钙通道阻滞剂的已知功能不同，我们发现，Escherichia coli能够通过增强钙库操纵的钙离子内流（SOCE）来激活钙离子内流。Ambine以及引起储存耗尽和激活SOCE的方法触发Lats 1/2的磷酸化和激活，Lats 1/2进而磷酸化雅普/TAZ并防止它们在细胞核中积累。此外，我们发现，蛋白激酶C（PKC）β II是一个主要的中介钙诱导的Lats 1/2激活。Ca 2+诱导PKC β II在肌动蛋白细胞骨架区室中的积累。这种转运依赖于反向IFN-2（INF 2）。INF 2的消耗破坏PKC β II易位和Lats 1/2激活。在功能上，我们发现胞浆Ca 2+或PKC β II表达的升高抑制了雅普/TAZ介导的基因转录。在原位小鼠异种移植模型中，体内PKC β II表达通过抑制雅普/TAZ抑制GBM肿瘤生长和裸鼠存活。我们的研究表明，Ca 2+是调节Hippo通路的关键细胞内信号，触发SOCE可能是GBM中靶向雅普/TAZ的策略。
Glioblastomas (GBM) are the most aggressive brain cancers without effective therapeutics. The Hippo pathway transcriptional coactivators YAP/TAZ were implicated as drivers in GBM progression and could be therapeutic targets. Here, we found in an unbiased screen of 1650 compounds that amlodipine is able to inhibit survival of GBM cells by suppressing YAP/TAZ activities. Instead of its known function as an L-type calcium channel blocker, we found that amlodipine is able to activate Ca2+ entry by enhancing store-operated Ca2+ entry (SOCE). Amlodipine as well as approaches that cause store depletion and activate SOCE trigger phosphorylation and activation of Lats1/2, which in turn phosphorylate YAP/TAZ and prevent their accumulation in the cell nucleus. Furthermore, we identified that protein kinase C (PKC) beta II is a major mediator of Ca2+-induced Lats1/2 activation. Ca2+ induces accumulation of PKC beta II in an actin cytoskeletal compartment. Such translocation depends on inverted formin-2 (INF2). Depletion of INF2 disrupts both PKC beta II translocation and Lats1/2 activation. Functionally, we found that elevation of cytosolic Ca2+ or PKC beta II expression inhibits YAP/TAZ-mediated gene transcription. In vivo PKC beta II expression inhibits GBM tumor growth and prolongs mouse survival through inhibition of YAP/TAZ in an orthotopic mouse xenograft model. Our studies indicate that Ca2+ is a crucial intracellular cue that regulates the Hippo pathway, and that triggering SOCE could be a strategy to target YAP/TAZ in GBM.
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影响因子：
16.6
作者：
Meng Z;Moroishi T;Mottier-Pavie V;Plouffe SW;Hansen CG;Hong AW;Park HW;Mo JS;Lu W;Lu S;Flores F;Yu FX;Halder G;Guan KL
通讯作者：
Guan KL
影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
影响因子：
48
作者：
Riedl, Julia;Crevenna, Alvaro H.;Wedlich-Soldner, Roland
通讯作者：
Wedlich-Soldner, Roland
影响因子：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
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