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Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ

Oncogene (2018) | Download Citation

Abstract

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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Acknowledgements

We thank Thomas Abraham and Wade Edris in the Microscopy Imaging Core Facility, Kang Li in the Molecular and Histopathology Core Facility, and Wesley Raup-Konsavage in the Drug Discovery, Development and Delivery Core Facility of Penn State College of Medicine for technical support and sample analysis. This work was supported by the National Institutes of Health MSTP Grant 5T32GM118294 (to P.P.Y. through PSU), National Institutes of Health Grants R01HL097111 and R01HL123364 (to M.T.), K22 5K22CA190440 (to W.L.), AACR-Aflac, Inc. Career Development Award for Pediatric Cancer Research 14-20-10-LI (to W.L.), and the Four Diamonds Fund for Pediatric Cancer Research (to W.L.).

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Affiliations

  1. Division of Pediatric Hematology/Oncology, Department of Pediatrics, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA

    • Zhijun Liu
    • , Yiju Wei
    • , Lei Zhang
    • , Patricia P. Yee
    • , Melissa Gulley
    • , Jennifer M. Atkinson
    • , Hong-Gang Wang
    •  & Wei Li
  2. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    • Lei Zhang
  3. Department of Cellular & Molecular Physiology, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA

    • Martin Johnson
    • , Xuexin Zhang
    •  & Mohamed Trebak
  4. Department of Pharmacology, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA

    • Hong-Gang Wang
  5. Department of Biochemistry & Molecular Biology, Penn State Health Hershey Medical Center, Penn State College of Medicine, Hershey, PA, 17033, USA

    • Wei Li

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The authors declare that they have no conflict of interest.

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Correspondence to Wei Li.

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https://doi.org/10.1038/s41388-018-0425-7