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TMEM164 enhances radioresistance of GBM cells by inhibiting the FASN-NADPH-ROS axis
Zhaoyan Jiang1, Xiaoya Jin1, Hetian Xue1
1Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Purpose:
Glioblastoma multiforme (GBM), one of the most aggressive primary brain malignancies, remains a major therapeutic challenge in contemporary neuro-oncology. Radiotherapy, an essential component of current standard therapeutic protocol, still has persistently poor clinical efficacy in the intrinsic radioresistance of GBM. Therefore, elucidating the underlying mechanisms of radioresistance is critical for optimizing therapeutic outcomes in GBM patients.
Methods:
Radioresistant GBM cell lines U251R were established by irradiating U251 cells with fractionated dose of 60 Gy in total. RNA-seq and TMT assays were applied, combined with GEO, KEGG and other databases to analyze the role of TMEM164 in regulating the radiosensitivity of GBM cells. Pharmacological inhibition of cell death pathways was employed to identify the predominant cell death mechanism influencing TMEM164-mediated radioresistance in GBM cells. The intracellular levels of NADPH, lipid droplet and ROS were detected after radiation to assess the effect of TMEM164 on lipid metabolism. The effect of TMEM164 on necroptosis through FASN-NADPH-ROS axis was verified by rescue experiments.
Results:
Through bioinformatics analysis, TMEM164 was identified as a key gene regulating GBM cells' radiosensitivity. Knockdown of TMEM164 significantly increased necroptosis in U251R and T98G cells. Integrated enrichment analysis of RNA-seq and TMT data revealed that FASN interacted with TMEM164. Excessive NADPH consumption led to intracellular ROS accumulation, thereby increasing radiosensitivity in GBM cells.
Conclusions:
Our findings indicated that TMEM164 might serve as a critical biological target of GBM cells radioresistance, providing a novel theoretical basis for GBM radiotherapy.
Insights
TMEM164 is a key gene in glioblastoma multiforme radioresistance. Targeting TMEM164 enhances necroptosis and radiosensitivity by affecting the FASN-NADPH-ROS axis, offering a new strategy for glioblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer with poor outcomes.
- Intrinsic radioresistance limits the efficacy of radiotherapy in GBM treatment.
- Understanding radioresistance mechanisms is crucial for improving GBM patient therapy.
Purpose of the Study:
- To identify key genes regulating glioblastoma multiforme (GBM) radiosensitivity.
- To elucidate the role of TMEM164 in GBM radioresistance.
- To explore TMEM164's mechanism in regulating cell death and lipid metabolism.
Main Methods:
- Established radioresistant GBM cell lines (U251R) via fractionated irradiation.
- Utilized RNA-seq, TMT assays, and bioinformatics analysis to identify key genes.
- Investigated TMEM164's role in radiosensitivity, cell death, lipid metabolism, and ROS levels.
Main Results:
- TMEM164 identified as a critical gene influencing GBM radiosensitivity.
- TMEM164 knockdown increased necroptosis in radioresistant GBM cells.
- TMEM164 interacts with FASN, impacting NADPH consumption, ROS accumulation, and radiosensitivity.
Conclusions:
- TMEM164 is a potential therapeutic target for overcoming GBM radioresistance.
- The FASN-NADPH-ROS axis is implicated in TMEM164-mediated radioresistance.
- Findings provide a novel theoretical basis for enhancing GBM radiotherapy efficacy.
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