A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress

Joshua L. Katz; Yuheng Geng; Leah K. Billingham; Nishanth S. Sadagopan; Susan L. DeLay; Jay Subbiah; Tzu Yi Chia; Graysen McManus; Chao Wei; Hanxiang Wang; Hanchen Lin; Caylee Silvers; Lauren K. Boland; Si Wang; Hanxiao Wan; David Hou; Gustavo Ignacio Vázquez-Cervantes; Tarlan Arjmandi; Zainab H. Shaikh; Peng Zhang; Atique U. Ahmed; Deanna M. Tiek; Catalina Lee-Chang; Edward T. Chouchani; Jason Miska

doi:10.1038/s41598-024-73051-1

A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress

Joshua L. Katz, Yuheng Geng, Leah K. Billingham, Nishanth S. Sadagopan, Susan L. DeLay, Jay Subbiah, Tzu Yi Chia, Graysen McManus, Chao Wei, Hanxiang Wang, Hanchen Lin, Caylee Silvers, Lauren K. Boland, Si Wang, Hanxiao Wan, David Hou, Gustavo Ignacio Vázquez-Cervantes, Tarlan Arjmandi, Zainab H. Shaikh, Peng ZhangAtique U. Ahmed, Deanna M. Tiek, Catalina Lee-Chang, Edward T. Chouchani, Jason Miska^*

^*Corresponding author for this work

Neurological Surgery

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

1 Scopus citations

Abstract

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

Original language	English (US)
Article number	21959
Journal	Scientific reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-73051-1
State	Published - Dec 2024

Funding

This was funded by National Institutes of Health/NCI grant (JM) \u2212\u20091R01CA279686-01, National Institutes of Health/NCI grant P50CA221747 (MSL, JM) SPORE subaward, National Institutes of Health/R01NS096376-06A1 1R01CA223547-01. We would like to thank Prof. Ben-Sahra (Northwestern) for his assistance in the development and analyses of the 13\u00A0C-flux studies. We would like to thank Navdeep Chandel (Northwestern) for his advice and collaboration on this work.

Keywords

Brain tumor
Cell migration
Enzyme inhibitor
Oxidative stress
Tumor metabolism

ASJC Scopus subject areas

General

UN SDGs

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

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10.1038/s41598-024-73051-1

Cite this

Katz, J. L., Geng, Y., Billingham, L. K., Sadagopan, N. S., DeLay, S. L., Subbiah, J., Chia, T. Y., McManus, G., Wei, C., Wang, H., Lin, H., Silvers, C., Boland, L. K., Wang, S., Wan, H., Hou, D., Vázquez-Cervantes, G. I., Arjmandi, T., Shaikh, Z. H., ... Miska, J. (2024). A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress. Scientific reports, 14(1), Article 21959. https://doi.org/10.1038/s41598-024-73051-1

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title = "A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress",

abstract = "Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.",

keywords = "Brain tumor, Cell migration, Enzyme inhibitor, Oxidative stress, Tumor metabolism",

author = "Katz, {Joshua L.} and Yuheng Geng and Billingham, {Leah K.} and Sadagopan, {Nishanth S.} and DeLay, {Susan L.} and Jay Subbiah and Chia, {Tzu Yi} and Graysen McManus and Chao Wei and Hanxiang Wang and Hanchen Lin and Caylee Silvers and Boland, {Lauren K.} and Si Wang and Hanxiao Wan and David Hou and V{\'a}zquez-Cervantes, {Gustavo Ignacio} and Tarlan Arjmandi and Shaikh, {Zainab H.} and Peng Zhang and Ahmed, {Atique U.} and Tiek, {Deanna M.} and Catalina Lee-Chang and Chouchani, {Edward T.} and Jason Miska",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41598-024-73051-1",

language = "English (US)",

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Katz, JL, Geng, Y, Billingham, LK, Sadagopan, NS, DeLay, SL, Subbiah, J, Chia, TY, McManus, G, Wei, C, Wang, H, Lin, H, Silvers, C, Boland, LK, Wang, S, Wan, H, Hou, D, Vázquez-Cervantes, GI, Arjmandi, T, Shaikh, ZH, Zhang, P , Ahmed, AU, Tiek, DM, Lee-Chang, C, Chouchani, ET & Miska, J 2024, 'A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress', Scientific reports, vol. 14, no. 1, 21959. https://doi.org/10.1038/s41598-024-73051-1

TY - JOUR

T1 - A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress

AU - Katz, Joshua L.

AU - Geng, Yuheng

AU - Billingham, Leah K.

AU - Sadagopan, Nishanth S.

AU - DeLay, Susan L.

AU - Subbiah, Jay

AU - Chia, Tzu Yi

AU - McManus, Graysen

AU - Wei, Chao

AU - Wang, Hanxiang

AU - Lin, Hanchen

AU - Silvers, Caylee

AU - Boland, Lauren K.

AU - Wang, Si

AU - Wan, Hanxiao

AU - Hou, David

AU - Vázquez-Cervantes, Gustavo Ignacio

AU - Arjmandi, Tarlan

AU - Shaikh, Zainab H.

AU - Zhang, Peng

AU - Ahmed, Atique U.

AU - Tiek, Deanna M.

AU - Lee-Chang, Catalina

AU - Chouchani, Edward T.

AU - Miska, Jason

PY - 2024/12

Y1 - 2024/12

N2 - Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

AB - Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

KW - Brain tumor

KW - Cell migration

KW - Enzyme inhibitor

KW - Oxidative stress

KW - Tumor metabolism

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A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress

Abstract

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UN SDGs

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