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

Subhas Mukherjee*, Carol Tucker-Burden, Emily Kaissi, Austin Newsam, Hithardhi Duggireddy, Monica Chau, Changming Zhang, Bhakti Diwedi, Manali Rupji, Sandra Seby, Jeanne Kowalski, Jun Kong, Renee Read, Daniel J. Brat

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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. Glioblastoma is the most common and deadliest form of brain tumor and can withstand current therapies due to the resilience of glioma stem cells (GSCs). Mukherjee et al. examine Cdk5 and its role in promoting stemness in asymmetric division of brain tumor stem cells in Drosophila and mice.

Original languageEnglish (US)
Pages (from-to)1651-1664
Number of pages14
JournalCell Reports
Volume23
Issue number6
DOIs
StatePublished - May 8 2018

Keywords

  • asymmetric cell division
  • CDK5
  • CREB1
  • GBM non-mesenchymal subtypes
  • glioma stem cells
  • self-renewal

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells'. Together they form a unique fingerprint.

Cite this