» Articles » PMID: 30082911

Induction of Store-operated Calcium Entry (SOCE) Suppresses Glioblastoma Growth by Inhibiting the Hippo Pathway Transcriptional Coactivators YAP/TAZ

Overview
Journal Oncogene
Date 2018 Aug 8
PMID 30082911
Citations 43
Authors
Affiliations
Soon will be listed here.
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 Ca entry by enhancing store-operated Ca 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 Ca-induced Lats1/2 activation. Ca 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 Ca 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 Ca is a crucial intracellular cue that regulates the Hippo pathway and that triggering SOCE could be a strategy to target YAP/TAZ in GBM.

Citing Articles

Regulation of formin INF2 and its alteration in INF2-linked inherited disorders.

Labat-de-Hoz L, Jimenez M, Correas I, Alonso M Cell Mol Life Sci. 2024; 81(1):463.

PMID: 39586895 PMC: 11589041. DOI: 10.1007/s00018-024-05499-3.


A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells.

Hikasa H, Kawahara K, Inui M, Yasuki Y, Yamashita K, Otsubo K Cancer Sci. 2024; 115(10):3370-3383.

PMID: 39155534 PMC: 11447953. DOI: 10.1111/cas.16316.


The Reappraisal of the Reappraisal-CRAC Channels Are Activated by L-Type Ca Channel Blockers, Reply to Bird et al.

Trebak M, Machaca K, Hogan P Function (Oxf). 2024; 5(2):zqae007.

PMID: 38486979 PMC: 10935452. DOI: 10.1093/function/zqae007.


Construction of disulfidptosis-based immune response prediction model with artificial intelligence and validation of the pivotal grouping oncogene c-MET in regulating T cell exhaustion.

Li P, Wang S, Wan H, Huang Y, Yin K, Sun K Front Immunol. 2024; 15:1258475.

PMID: 38352883 PMC: 10862485. DOI: 10.3389/fimmu.2024.1258475.


Ca signaling and the Hippo pathway: Intersections in cellular regulation.

Sayedyahossein S, Thines L, Sacks D Cell Signal. 2023; 110:110846.

PMID: 37549859 PMC: 10529277. DOI: 10.1016/j.cellsig.2023.110846.


References
1.
Blobe G, Stribling D, Fabbro D, Stabel S, Hannun Y . Protein kinase C beta II specifically binds to and is activated by F-actin. J Biol Chem. 1996; 271(26):15823-30. DOI: 10.1074/jbc.271.26.15823. View

2.
Monteith G, Prevarskaya N, Roberts-Thomson S . The calcium-cancer signalling nexus. Nat Rev Cancer. 2017; 17(6):367-380. DOI: 10.1038/nrc.2017.18. View

3.
Shao D, Xue W, Krall E, Bhutkar A, Piccioni F, Wang X . KRAS and YAP1 converge to regulate EMT and tumor survival. Cell. 2014; 158(1):171-84. PMC: 4110062. DOI: 10.1016/j.cell.2014.06.004. View

4.
Wales P, Schuberth C, Aufschnaiter R, Fels J, Garcia-Aguilar I, Janning A . Calcium-mediated actin reset (CaAR) mediates acute cell adaptations. Elife. 2016; 5. PMC: 5140269. DOI: 10.7554/eLife.19850. View

5.
Trebak M, Bird G, McKay R, Putney Jr J . Comparison of human TRPC3 channels in receptor-activated and store-operated modes. Differential sensitivity to channel blockers suggests fundamental differences in channel composition. J Biol Chem. 2002; 277(24):21617-23. DOI: 10.1074/jbc.M202549200. View