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

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 a...

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Autores principales: Liu, Zhijun, Wei, Yiju, Zhang, Lei, Yee, Patricia P., Johnson, Martin, Zhang, Xuexin, Gulley, Melissa, Xavier, Jennifer, Trebak, Mohamed, Wang, Hong-Gang, Li, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318057/
https://www.ncbi.nlm.nih.gov/pubmed/30082911
http://dx.doi.org/10.1038/s41388-018-0425-7
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author Liu, Zhijun
Wei, Yiju
Zhang, Lei
Yee, Patricia P.
Johnson, Martin
Zhang, Xuexin
Gulley, Melissa
Xavier, Jennifer
Trebak, Mohamed
Wang, Hong-Gang
Li, Wei
author_facet Liu, Zhijun
Wei, Yiju
Zhang, Lei
Yee, Patricia P.
Johnson, Martin
Zhang, Xuexin
Gulley, Melissa
Xavier, Jennifer
Trebak, Mohamed
Wang, Hong-Gang
Li, Wei
author_sort Liu, Zhijun
collection PubMed
description 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(2+) entry by enhancing store-operated Ca(2+) 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(2+)-induced Lats1/2 activation. Ca(2+) 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(2+) 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(2+) 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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spelling pubmed-63180572019-02-06 Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ Liu, Zhijun Wei, Yiju Zhang, Lei Yee, Patricia P. Johnson, Martin Zhang, Xuexin Gulley, Melissa Xavier, Jennifer Trebak, Mohamed Wang, Hong-Gang Li, Wei Oncogene Article 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(2+) entry by enhancing store-operated Ca(2+) 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(2+)-induced Lats1/2 activation. Ca(2+) 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(2+) 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(2+) is a crucial intracellular cue that regulates the Hippo pathway, and that triggering SOCE could be a strategy to target YAP/TAZ in GBM. 2018-08-06 2019-01 /pmc/articles/PMC6318057/ /pubmed/30082911 http://dx.doi.org/10.1038/s41388-018-0425-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Liu, Zhijun
Wei, Yiju
Zhang, Lei
Yee, Patricia P.
Johnson, Martin
Zhang, Xuexin
Gulley, Melissa
Xavier, Jennifer
Trebak, Mohamed
Wang, Hong-Gang
Li, Wei
Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
title Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
title_full Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
title_fullStr Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
title_full_unstemmed Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
title_short Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
title_sort induction of store operated calcium entry (soce) suppresses glioblastoma growth by inhibiting the hippo pathway transcriptional coactivators yap/taz
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318057/
https://www.ncbi.nlm.nih.gov/pubmed/30082911
http://dx.doi.org/10.1038/s41388-018-0425-7
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