GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair

Hui Xu, Jing Jin, Ying Chen, Guoqing Wu, Hua Zhu, Qing Wang, Ji Wang, Shenggang Li, Florina Nicoleta Grigore, Jun Ma, Clark C. Chen, Qing Lan, Ming Li

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3876-3885
Number of pages10
JournalOncogene
Volume41
Issue number31
DOIs
StatePublished - Jul 29 2022

Bibliographical note

Funding Information:
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).

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

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