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

• Type of Material: Conference Paper
• Authors: Subbhas Mukherjee, Northwestern University; Carol Tucker-Burden, Emory University; Emily Kaissi, Emory University; Austin Newsam, Center for Disease Control and Prevention; Hithardhi Duggireddy, Emory University; Monica Chau, University of Kentucky; Changming Zhang, The First Affiliated Hospital of Sun Yat-sen University; Bhakti Diwedi, Emory University; Manali Rupji, Emory University; Sandra Seby, Emory University; Jeanne Kowalski, Emory University; Jun Kong, Emory University; Renee D. Read, Emory University; Daniel J Brat, Emory University
• Language: English
• Date: 2018-05-08
• Publisher: Emory University Libraries
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2018.04.016
• Title of Journal or Parent Work: CELL REPORTS
• Volume: 23
• Issue: 6
• Start Page: 1651
• End Page: 1664
• Grant/Funding Information: This work was also supported by US Public Health Service NIH (R01 CA176659 and CA149107 to D.J.B. and K25CA181503 to J.K.), the Win-ship Cancer Institute NCI Cancer Center (P30CA138292), and the Georgia Research Alliance (to D.J.B.).
• Keywords: CYCLIN-DEPENDENT KINASE-5; Life Sciences & Biomedicine; DROSOPHILA; DIVISION; BRAIN; Science & Technology; GLIOBLASTOMA; GENE ACTIVATION; ORTHOLOG TRIM3; PHOSPHORYLATION; Cell Biology; TUMOR BIOLOGY; REGULATED KINASE
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Bioinformatics; Health Sciences, Pathology

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.