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.

中文翻译：

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通过抑制Hippo途径转录共激活因子YAP / TAZ，诱导钙离子操纵的钙进入（SOCE）抑制胶质母细胞瘤的生长。

胶质母细胞瘤（GBM）是没有有效疗法的最具侵略性的脑癌。Hippo途径转录共激活因子YAP / TAZ被认为是GBM进展的驱动因素，可能是治疗靶点。在这里，我们在1650种化合物的无偏筛选中发现，氨氯地平能够通过抑制YAP / TAZ活性来抑制GBM细胞的存活。我们发现氨氯地平不是通过增强L型钙通道阻滞剂的已知功能，而是可以通过增强贮藏操作的Ca ²⁺来激活Ca ²⁺进入。条目（SOCE）。氨氯地平以及引起存储耗尽并激活SOCE的方法会触发Lats1 / 2的磷酸化和激活，进而使YAP / TAZ磷酸化并阻止其在细胞核中积累。此外，我们发现蛋白激酶C（PKC）beta II是Ca ²⁺诱导的Lats1 / 2激活的主要介质。Ca ²⁺诱导肌动蛋白细胞骨架^区隔中的PKCβII的积累。这种易位依赖于倒转的formin-2（INF2）。INF2的消耗会破坏PKC beta II易位和Lats1 / 2激活。在功能上，我们发现胞质Ca ^2+的升高或PKC beta II表达抑制YAP / TAZ介导的基因转录。在原位小鼠异种移植模型中，体内PKC beta II表达通过抑制YAP / TAZ抑制GBM肿瘤生长并延长小鼠存活期。我们的研究表明，Ca ²⁺是调节Hippo途径的关键细胞内线索，而触发SOCE可能是靶向GBM中YAP / TAZ的策略。