2. Academic Validation
  3. CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells

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

Affiliations

  • 1 Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: subhas.mukherjee@northwestern.edu.
  • 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: daniel.brat@northwestern.edu.
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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