CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells

Cell Rep. 2018 May 8;23(6):1651-1664. doi: 10.1016/j.celrep.2018.04.016.

Abstract

Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP. Finally, our TCGA GBM data analysis revealed that CDK5, stem cell, and asymmetric cell division markers segregate within non-mesenchymal patient clusters, which may indicate preferential dependence on CDK5 signaling and sensitivity to its inhibition in this group.

Keywords: CDK5; CREB1; GBM non-mesenchymal subtypes; asymmetric cell division; glioma stem cells; self-renewal.

Publication types

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

MeSH terms

  • Animals
  • Asymmetric Cell Division / drug effects
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cell Self Renewal / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism
  • Drosophila Proteins / antagonists & inhibitors*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology*
  • Mesoderm / drug effects
  • Mesoderm / pathology
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction*
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Cyclic AMP Response Element-Binding Protein
  • Drosophila Proteins
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Cyclin-Dependent Kinase 5
  • Cyclic AMP-Dependent Protein Kinases
  • CDK5 protein, human
  • Cdk5 protein, Drosophila