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

Cell Reports (May 2018)

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

Affiliations

Subhas Mukherjee: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding author
Carol Tucker-Burden: Department of Hematology and Oncology, Emory University, Atlanta, GA 30322, USA
Emily Kaissi: Department of Pediatrics, Emory University, Atlanta, GA 30322, USA
Austin Newsam: Division of Parasitic Diseases and Malaria, Center for Disease Control and Prevention, Atlanta, GA, USA
Hithardhi Duggireddy: Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA
Monica Chau: Department of Neurology, University of Kentucky, Lexington, KY, USA
Changming Zhang: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Bhakti Diwedi: Winship Cancer Institute Bioinformatics Core, Emory University, Atlanta, GA 30322, USA
Manali Rupji: Winship Cancer Institute Bioinformatics Core, Emory University, Atlanta, GA 30322, USA
Sandra Seby: Winship Cancer Institute Bioinformatics Core, Emory University, Atlanta, GA 30322, USA
Jeanne Kowalski: Winship Cancer Institute Bioinformatics Core, Emory University, Atlanta, GA 30322, USA
Jun Kong: Department of Bioinformatics, Emory University, Atlanta, GA 30322, USA
Renee Read: Department of Pharmacology, Emory University, Atlanta, GA 30322, USA
Daniel J. Brat: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding author

Journal volume & issue: Vol. 23, no. 6
pp. 1651 – 1664

Abstract

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

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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