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Published on: March 28, 2021
TRIM67 Suppresses Glioblastoma Glycolysis and Increases Temozolomide Sensitivity by Promoting ARSD Ubiquitinated
Xuzhao Li1,2, Fangzhou Guo3, Lixin Xu2
1Graduate School, Dalian Medical University, Dalian, Liaoning Province, People's Republic of China.
Abstract:
Glioblastoma (GBM) is one of the deadliest malignant tumors in the central nervous system. Temozolomide (TMZ) resistance is a crucial cause of treatment failure in GBM. We intended to explore the molecular mechanisms by which ARSD modulated TMZ resistance in GBM. This study revealed that ARSD was up-regulated in GBM and associated with GBM recurrence and poor prognosis. Furthermore, knockdown of ARSD suppressed glycolysis and increased TMZ sensitivity in GBM cells. Mechanistic insights demonstrated that TRIM67 promoted the ubiquitinated degradation of ARSD through the RING structural domain. Concurrently, overexpression of TRIM67 repressed GBM cell glycolysis and increased sensitivity to TMZ by decreasing ARSD expression. Additionally, TRIM67 down-regulated ARSD to hinder β-catenin-mediated glycolysis in GBM cells and suppressed tumor growth in nude mice. Taken together, TRIM67 suppresses ARSD expression by facilitating its ubiquitin-mediated degradation, thereby inactivating the β-catenin pathway to repress GBM glycolysis and TMZ resistance. This study reveals the TRIM67/ARSD/β-catenin axis as a key regulator of GBM metabolic reprogramming and TMZ resistance, offering a novel therapeutic target.
Insights
This study reveals TRIM67 targets ARSD for degradation, reducing glioblastoma (GBM) glycolysis and temozolomide (TMZ) resistance. This finding offers a new therapeutic strategy for treating aggressive brain tumors like GBM.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis.
- Temozolomide (TMZ) resistance significantly limits treatment efficacy in GBM patients.
- Understanding the molecular mechanisms of TMZ resistance is critical for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of ARSD in modulating TMZ resistance in GBM.
- To elucidate the molecular mechanisms by which TRIM67 affects ARSD expression and GBM progression.
- To identify potential therapeutic targets for overcoming TMZ resistance in GBM.
Main Methods:
- Analysis of ARSD expression in GBM tissues and correlation with prognosis.
- In vitro studies involving knockdown and overexpression of ARSD and TRIM67 in GBM cells.
- Investigation of glycolysis, ubiquitinated degradation, and the β-catenin pathway.
- In vivo tumor growth studies in nude mice.
Main Results:
- ARSD is upregulated in GBM and linked to recurrence and poor survival.
- Knockdown of ARSD reduces glycolysis and enhances TMZ sensitivity in GBM cells.
- TRIM67 promotes ARSD degradation, suppressing glycolysis and increasing TMZ sensitivity.
- The TRIM67/ARSD/β-catenin axis regulates GBM metabolism and TMZ resistance.
Conclusions:
- TRIM67 suppresses ARSD expression via ubiquitin-mediated degradation.
- Inactivation of the β-catenin pathway by TRIM67 reduces GBM glycolysis and TMZ resistance.
- The TRIM67/ARSD/β-catenin pathway represents a novel therapeutic target for GBM treatment.
