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

Oncogene. 2019 Jan;38(1):120-139. doi: 10.1038/s41388-018-0425-7. Epub 2018 Aug 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics
  • Amlodipine / pharmacology*
  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology*
  • Calcium Signaling / drug effects*
  • Calcium Signaling / physiology
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Gene Knockdown Techniques
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Ionomycin / pharmacology
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • ORAI1 Protein / antagonists & inhibitors
  • ORAI1 Protein / genetics
  • ORAI1 Protein / physiology
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / genetics
  • Phosphorylation / drug effects
  • Protein Kinase C beta / physiology
  • Protein Kinases / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Thapsigargin / pharmacology
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium Channel Blockers
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Phosphoproteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • TAZ protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Amlodipine
  • Ionomycin
  • Thapsigargin
  • Protein Kinases
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Protein Kinase C beta
  • Calcium