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.
Subhas Mukherjee  1 ,  Carol Tucker-Burden  2 ,  Emily Kaissi  3 ,  Austin Newsam  4 ,  Hithardhi Duggireddy  5 ,  Monica Chau  6 ,  Changming Zhang  7 ,  Bhakti Diwedi  8 ,  Manali Rupji  8 ,  Sandra Seby  8 ,  Jeanne Kowalski  8 ,  Jun Kong  9 ,  Renee Read  10 ,  Daniel J Brat  11
Affiliations
  • 1. Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].
  • 2. Department of Hematology and Oncology, Emory University, Atlanta, GA 30322, USA.
  • 3. Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
  • 4. Division of Parasitic Diseases and Malaria, Center for Disease Control and Prevention, Atlanta, GA, USA.
  • 5. Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.
  • 6. Department of Neurology, University of Kentucky, Lexington, KY, USA.
  • 7. Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 8. Winship Cancer Institute Bioinformatics Core, Emory University, Atlanta, GA 30322, USA.
  • 9. Department of Bioinformatics, Emory University, Atlanta, GA 30322, USA.
  • 10. Department of Pharmacology, Emory University, Atlanta, GA 30322, USA.
  • 11. Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 29742423 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.
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