Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma
Summary: 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 ha...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225000288 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Deanna Tiek |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-1418c789191844b89910ef5e7253e8c1 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-1418c789191844b89910ef5e7253e8c12025-01-31T05:12:11ZengElsevieriScience2589-00422025-02-01282111769Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastomaDeanna Tiek0Xiao Song1Xiaozhou Yu2Runxin Wu3Rebeca Iglesia4Alicia Catezone5Katy McCortney6Jordain Walshon7Craig Horbinski8Pouya Jamshidi9Rudolph Castellani10Robert Vassar11Jason Miska12Bo Hu13Shi-Yuan Cheng14The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding authorThe Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartments of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Pathology, Northwestern University Feinberg School of Medicine, The Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Chicago, IL 60611, USADepartment of Pathology, Northwestern University Feinberg School of Medicine, The Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Chicago, IL 60611, USAThe Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, The Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Chicago, IL 60611, USADepartment of Neurosurgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004225000288Biological sciencesNeuroscienceMolecular neuroscienceCancer |
| spellingShingle | 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 Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma iScience Biological sciences Neuroscience Molecular neuroscience Cancer |
| title | Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma |
| title_full | Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma |
| title_fullStr | Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma |
| title_full_unstemmed | Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma |
| title_short | Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma |
| title_sort | oxidative stress induced protein aggregation via ggct produced pyroglutamic acid in drug resistant glioblastoma |
| topic | Biological sciences Neuroscience Molecular neuroscience Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225000288 |
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