GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair

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.

Automated summary

This study reveals that the expression of interferon inducible guanylate binding protein 3 (GBP3) and stimulator of interferon genes (STING) is upregulated by Temozolomide (TMZ) treatment, contributing to TMZ resistance in glioblastoma. GBP3 physically interacts with STING and stabilizes its protein levels, leading to the expression of genes associated with resistance. Targeting GBP3 could enhance the sensitivity of glioblastoma to TMZ treatment. Clinically, high expression of GBP3 is correlated with poor outcomes in glioblastoma patients.