GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair.

Animals Antineoplastic Agents, Alkylating / pharmacology Brain Neoplasms / drug therapy Cell Line, Tumor DNA Damage DNA Modification Methylases / genetics DNA Repair Enzymes / genetics Drug Resistance, Neoplasm / genetics GTP-Binding Proteins / metabolism Glioblastoma / drug therapy Humans Interferons / genetics Mice NF-E2-Related Factor 2 / genetics Temozolomide / pharmacology

Journal

Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562

Informations de publication

Date de publication:
07 2022
Historique:
received: 19 11 2021
accepted: 21 06 2022
revised: 15 06 2022
pubmed: 3 7 2022
medline: 3 8 2022
entrez: 2 7 2022
Statut: ppublish

Résumé

Glioblastoma is the most common malignant brain cancer with dismal survival and prognosis. Temozolomide (TMZ) is a first-line chemotherapeutic agent for glioblastoma, but the emergence of drug resistance limits its anti-tumor activity. We previously discovered that the interferon inducible guanylate binding protein 3 (GBP3) is highly elevated and promotes tumorigenicity of glioblastoma. Here, we show that TMZ treatment significantly upregulates the expression of GBP3 and stimulator of interferon genes (STING), both of which increase TMZ-induced DNA damage repair and reduce cell apoptosis of glioblastoma cells. Mechanistically, relying on its N-terminal GTPase domain, GBP3 physically interacts with STING to stabilize STING protein levels, which in turn induces expression of p62 (Sequestosome 1), nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and O6-methlyguanine-DNA-methyltransferase (MGMT), leading to the resistance to TMZ treatment. Reducing GBP3 levels by RNA interference in glioblastoma cells markedly increases the sensitivity to TMZ treatment in vitro and in murine glioblastoma models. Clinically, GBP3 expression is high and positively correlated with STING, NRF2, p62, and MGMT expression in human glioblastoma tumors, and is associated with poor outcomes. These findings provide novel insight into TMZ resistance and suggest that GBP3 may represent a novel potential target for the treatment of glioblastoma.

Identifiants

DOI: 10.1038/s41388-022-02397-5 PMID: 35780181
pubmed: 35780181
doi: 10.1038/s41388-022-02397-5
pii: 10.1038/s41388-022-02397-5
doi:

Substances chimiques

Antineoplastic Agents, Alkylating 0
GBP3 protein, human 0
Gbp3 protein, mouse 0
NF-E2-Related Factor 2 0
Interferons 9008-11-1
DNA Modification Methylases EC 2.1.1.-
GTP-Binding Proteins EC 3.6.1.-
DNA Repair Enzymes EC 6.5.1.-
Temozolomide YF1K15M17Y

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3876-3885

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Hui Xu (H)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.
Jiangsu Key Laboratory of Neuropsychiatric Disease, Institute of Neuroscience, Soochow University, Suzhou, 215004, Jiangsu, China.

Jing Jin (J)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.

Ying Chen (Y)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.

Guoqing Wu (G)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.

Hua Zhu (H)

Department of Pediatrics, The First Hospital of China Medical University, Shenyang, 110122, Liaoning, China.

Qing Wang (Q)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.

Ji Wang (J)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.

Shenggang Li (S)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China.

Florina-Nicoleta Grigore (FN)

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA.

Jun Ma (J)

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA.

Clark C Chen (CC)

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA.
ORCID: 0000-0001-9544-2570

Qing Lan (Q)

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, Jiangsu, China. szlq006@163.com.
Jiangsu Key Laboratory of Neuropsychiatric Disease, Institute of Neuroscience, Soochow University, Suzhou, 215004, Jiangsu, China. szlq006@163.com.
ORCID: 0000-0002-8468-4942

Ming Li (M)

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA. m2li@umn.edu.
ORCID: 0000-0002-2540-1738

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions toxiques › Noxas › Agents alcoylants › Antinéoplasiques alcoylants › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA modification methylases › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Enzymes de réparation de l'ADN › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Astrocytome › Glioblastome › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interférons › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteur-2 apparenté à NF-E2 › GBP3 promotes glioblastoma resistance to...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Dacarbazine › Témozolomide › GBP3 promotes glioblastoma resistance to...