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GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair

Abstract

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.

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Fig. 1: GBP3 is induced by TMZ and is associated with poor outcome in glioblastoma patients.
Fig. 2: GBP3 promotes glioblastoma cells resistance to TMZ in vitro.
Fig. 3: STING is induced by TMZ and participates in GBP3-promoted TMZ resistance.
Fig. 4: GBP3 interacts with STING to increase STING protein stabilization in glioblastoma cells.
Fig. 5: GBP3 and STING regulate p62/NRF2 axis and NRF2 reverses GBP3 knockdown induced TMZ sensitivity.
Fig. 6: The GBP3/STING/NRF2 axis regulates MGMT expression and enhances glioblastoma resistance to TMZ.
Fig. 7: GBP3 knockdown reduces glioblastoma tumorigenesis and enhances TMZ therapeutic efficacy in vivo.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81572480), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Key Laboratory of Minimally Invasive Neurosurgery of Suzhou (SZ2021262).

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Flow cytometry studies were performed by HX, JJ, and GW. In vivo animal studies and analyses were performed by HX, YC, and QW. In vitro studies were performed by HX, SL, and JW. Informatic analysis was performed by HX and HZ. All studies were conceived, directed, and analyzed by CCC, JM, QL, and ML. The manuscript was written by HX, FNG, and ML.

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Correspondence to Qing Lan or Ming Li.

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Xu, H., Jin, J., Chen, Y. et al. GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair. Oncogene 41, 3876–3885 (2022). https://doi.org/10.1038/s41388-022-02397-5

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