TY - JOUR
T1 - CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells
AU - Mukherjee, Subhas
AU - Tucker-Burden, Carol
AU - Kaissi, Emily
AU - Newsam, Austin
AU - Duggireddy, Hithardhi
AU - Chau, Monica
AU - Zhang, Changming
AU - Diwedi, Bhakti
AU - Rupji, Manali
AU - Seby, Sandra
AU - Kowalski, Jeanne
AU - Kong, Jun
AU - Read, Renee
AU - Brat, Daniel J.
N1 - Publisher Copyright:
© 2018 The Author(s)
PY - 2018/5/8
Y1 - 2018/5/8
N2 - 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.
AB - 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.
KW - CDK5
KW - CREB1
KW - GBM non-mesenchymal subtypes
KW - asymmetric cell division
KW - glioma stem cells
KW - self-renewal
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U2 - 10.1016/j.celrep.2018.04.016
DO - 10.1016/j.celrep.2018.04.016
M3 - Article
C2 - 29742423
AN - SCOPUS:85046171035
SN - 2211-1247
VL - 23
SP - 1651
EP - 1664
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -
