Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma

Deanna Tiek; Xiao Song; Xiaozhou Yu; Runxin Wu; Rebeca Iglesia; Alicia Catezone; Katy McCortney; Jordain Walshon; Craig Horbinski; Pouya Jamshidi; Rudolph Castellani; Robert Vassar; Jason Miska; Bo Hu; Shi Yuan Cheng

doi:10.1016/j.isci.2025.111769

Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma

Deanna Tiek^*, Xiao Song, Xiaozhou Yu, Runxin Wu, Rebeca Iglesia, Alicia Catezone, Katy McCortney, Jordain Walshon, Craig Horbinski, Pouya Jamshidi, Rudolph Castellani, Robert Vassar, Jason Miska, Bo Hu, Shi Yuan Cheng^*

^*Corresponding author for this work

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

Abstract

Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT—pyroglutamic acid—can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCT expression, and pyroglutamic acid staining in recurrent GBM patient samples, adjacent non-tumor brain, and Alzheimer's brains. These findings suggest a new pathway for protein aggregation within drug resistant brain cancer that should be further studied in other brain disorders.

Original language	English (US)
Article number	111769
Journal	iScience
Volume	28
Issue number	2
DOIs	https://doi.org/10.1016/j.isci.2025.111769
State	Published - Feb 21 2025

Funding

This work was supported by United States National Institutes of Health (NIH) grants, National Cancer Institute and Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine NS126810, NS125318, (S.-Y.C.); NCI CA234799 (D.T), CA279896 (D.T), United States Army Medical Research Acquisition Activity W81XWH-22-10373 (D.T.), W81XWH-22-1-0374 (X.S.). S.-Y.C. is a Zell Scholar at Northwestern University. The authors thank Northwestern University Feinberg School of Medicine Lurie Cancer Center Metabolomics Core and Northwestern Nervous System Tumor Bank (P50CA221747) and the Alzheimer's Disease Research Center (P30AG072977). This work was supported by United States National Institutes of Health (NIH) grants, National Cancer Institute and Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine NS126810 , NS125318 , (S.-Y.C.); NCI CA234799 (D.T), CA279896 (D.T), United States Army Medical Research Acquisition Activity W81XWH-22-10373 (D.T.), W81XWH-22-1-0374 (X.S.). S.-Y.C. is a Zell Scholar at Northwestern University . The authors thank Northwestern University Feinberg School of Medicine Lurie Cancer Center Metabolomics Core and Northwestern Nervous System Tumor Bank (P50CA221747) and the Alzheimer\u2019s Disease Research Center (P30AG072977).

Keywords

Biological sciences
Cancer
Molecular neuroscience
Neuroscience

ASJC Scopus subject areas

General

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10.1016/j.isci.2025.111769

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Tiek, D., Song, X., Yu, X., Wu, R., Iglesia, R., Catezone, A., McCortney, K., Walshon, J., Horbinski, C., Jamshidi, P., Castellani, R., Vassar, R., Miska, J., Hu, B., & Cheng, S. Y. (2025). Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma. iScience, 28(2), Article 111769. https://doi.org/10.1016/j.isci.2025.111769

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Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma

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