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

doi:10.1016/j.celrep.2018.04.016

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

Neurosurgery

Research output: Contribution to journal › Article › peer-review

27 Citations (SciVal)

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.

Original language	English
Pages (from-to)	1651-1664
Number of pages	14
Journal	Cell Reports
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2018.04.016
State	Published - May 8 2018

Bibliographical note

Funding Information:
We thank Drs. Kenneth Moberg, Erwin Van Meir, Zixu Mao, Adam Marcus (Winship Cancer Institute at Emory University), Mario Suva (Massachusetts General Hospital, Harvard University), and Monica Venere (Cleveland Clinic) for their valuable guidance. We thank Dr. Cheng-Yu Lee (Univ. of Michigan) for the Mira antibody. Our special thanks go to Drs. James Bibb (University of Alabama) and Dr. Karin Pozo (UT Southwestern) for advice on the CDK5 inhibitor CP681301. We thank Pfizer for providing the CDK5 inhibitor. We especially thank Dr. Ernestine Mahar, Dr. Edmund Waller, Dr. Melissa Gilbert-Ross, Dr. Anna Kenney, Dr. Neil Anthony, Dr. Abhinav Dey, Dr. Bing Yu, Dr. Debanjan Bhattacharya, Dr. Satoru Osuka, Zhaobin Zhang, Diane Alexis, and Jennifer Sheldon for their assistance with flow cytometry, confocal imaging, fly stocks, and mouse colony maintenance. Finally, we thank the Emory Integrated Cellular Imaging Core, Emory Cancer Pathology and Tissue Core, Winship Bioinformatics and Statistics Core facility, Bloomington Drosophila Stock Center, and the Division for Animal Resources for their advice and contributions to this manuscript. 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 Winship Cancer Institute NCI Cancer Center (P30CA138292), and the Georgia Research Alliance (to D.J.B.).

Funding Information:
We thank Drs. Kenneth Moberg, Erwin Van Meir, Zixu Mao, Adam Marcus (Winship Cancer Institute at Emory University), Mario Suva (Massachusetts General Hospital, Harvard University), and Monica Venere (Cleveland Clinic) for their valuable guidance. We thank Dr. Cheng-Yu Lee (Univ. of Michigan) for the Mira antibody. Our special thanks go to Drs. James Bibb (University of Alabama) and Dr. Karin Pozo (UT Southwestern) for advice on the CDK5 inhibitor CP681301. We thank Pfizer for providing the CDK5 inhibitor. We especially thank Dr. Ernestine Mahar, Dr. Edmund Waller, Dr. Melissa Gilbert-Ross, Dr. Anna Kenney, Dr. Neil Anthony, Dr. Abhinav Dey, Dr. Bing Yu, Dr. Debanjan Bhattacharya, Dr. Satoru Osuka, Zhaobin Zhang, Diane Alexis, and Jennifer Sheldon for their assistance with flow cytometry, confocal imaging, fly stocks, and mouse colony maintenance. Finally, we thank the Emory Integrated Cellular Imaging Core, Emory Cancer Pathology and Tissue Core, Winship Bioinformatics and Statistics Core facility, Bloomington Drosophila Stock Center, and the Division for Animal Resources for their advice and contributions to this manuscript. 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 Winship Cancer Institute NCI Cancer Center ( P30CA138292 ), and the Georgia Research Allianc e (to D.J.B.).

Publisher Copyright:
© 2018 The Author(s)

Keywords

CDK5
CREB1
GBM non-mesenchymal subtypes
asymmetric cell division
glioma stem cells
self-renewal

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2018.04.016

Cite this

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

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.",

keywords = "CDK5, CREB1, GBM non-mesenchymal subtypes, asymmetric cell division, glioma stem cells, self-renewal",

author = "Subhas Mukherjee and Carol Tucker-Burden and Emily Kaissi and Austin Newsam and Hithardhi Duggireddy and Monica Chau and Changming Zhang and Bhakti Diwedi and Manali Rupji and Sandra Seby and Jeanne Kowalski and Jun Kong and Renee Read and Brat, {Daniel J.}",

note = "Funding Information: We thank Drs. Kenneth Moberg, Erwin Van Meir, Zixu Mao, Adam Marcus (Winship Cancer Institute at Emory University), Mario Suva (Massachusetts General Hospital, Harvard University), and Monica Venere (Cleveland Clinic) for their valuable guidance. We thank Dr. Cheng-Yu Lee (Univ. of Michigan) for the Mira antibody. Our special thanks go to Drs. James Bibb (University of Alabama) and Dr. Karin Pozo (UT Southwestern) for advice on the CDK5 inhibitor CP681301. We thank Pfizer for providing the CDK5 inhibitor. We especially thank Dr. Ernestine Mahar, Dr. Edmund Waller, Dr. Melissa Gilbert-Ross, Dr. Anna Kenney, Dr. Neil Anthony, Dr. Abhinav Dey, Dr. Bing Yu, Dr. Debanjan Bhattacharya, Dr. Satoru Osuka, Zhaobin Zhang, Diane Alexis, and Jennifer Sheldon for their assistance with flow cytometry, confocal imaging, fly stocks, and mouse colony maintenance. Finally, we thank the Emory Integrated Cellular Imaging Core, Emory Cancer Pathology and Tissue Core, Winship Bioinformatics and Statistics Core facility, Bloomington Drosophila Stock Center, and the Division for Animal Resources for their advice and contributions to this manuscript. 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 Winship Cancer Institute NCI Cancer Center (P30CA138292), and the Georgia Research Alliance (to D.J.B.). Funding Information: We thank Drs. Kenneth Moberg, Erwin Van Meir, Zixu Mao, Adam Marcus (Winship Cancer Institute at Emory University), Mario Suva (Massachusetts General Hospital, Harvard University), and Monica Venere (Cleveland Clinic) for their valuable guidance. We thank Dr. Cheng-Yu Lee (Univ. of Michigan) for the Mira antibody. Our special thanks go to Drs. James Bibb (University of Alabama) and Dr. Karin Pozo (UT Southwestern) for advice on the CDK5 inhibitor CP681301. We thank Pfizer for providing the CDK5 inhibitor. We especially thank Dr. Ernestine Mahar, Dr. Edmund Waller, Dr. Melissa Gilbert-Ross, Dr. Anna Kenney, Dr. Neil Anthony, Dr. Abhinav Dey, Dr. Bing Yu, Dr. Debanjan Bhattacharya, Dr. Satoru Osuka, Zhaobin Zhang, Diane Alexis, and Jennifer Sheldon for their assistance with flow cytometry, confocal imaging, fly stocks, and mouse colony maintenance. Finally, we thank the Emory Integrated Cellular Imaging Core, Emory Cancer Pathology and Tissue Core, Winship Bioinformatics and Statistics Core facility, Bloomington Drosophila Stock Center, and the Division for Animal Resources for their advice and contributions to this manuscript. 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 Winship Cancer Institute NCI Cancer Center ( P30CA138292 ), and the Georgia Research Allianc e (to D.J.B.). Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2018",

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doi = "10.1016/j.celrep.2018.04.016",

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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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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