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KIF4A Inhibits Ferroptosis in Glioblastoma via the CHMP4B/GPX4 Axis and Promotes Temozolomide Resistance
Xinan Shen1,2, Honglei Cheng3, Jiarong Zheng1,2
1Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Temozolomide (TMZ) stands for the first-line chemotherapeutic agent against GBM. TMZ resistance is an important factor contributing to the poor prognosis of GBM, but the underlying molecular mechanisms are unclear. Previous studies have suggested that KIF4A may be an indicator of poor prognosis in glioma patients, but the association of KIF4A with TMZ resistance has never been investigated. The detection of ferroptosis levels in GBM cells was accomplished through the utilization of ROS, MDA, JC-1, and Western blot analysis. The assessment of TMZ resistance was performed through the implementation of CCK8, cell cloning, and cell cycle analysis. The identification of downstream targets of KIF4A was facilitated by protein profiling and immunofluorescence. KIF4A inhibits ferroptosis in GBM cells through the CHMP4B/GPX4 axis and promotes TMZ resistance. Knockdown of KIF4A or CHMP4B sensitized GBM cells to chemotherapy. In addition, KIF4A induced epithelial-mesenchymal transition in GBM cells, which synergistically promoted TMZ resistance.The present study elucidates a novel mechanism of TMZ resistance in glioblastoma through the CHMP4B/GPX4 axis. Based on these findings, targeting KIF4A may offer a potential new strategy against GBM.
Insights
Kinesin 4A (KIF4A) promotes temozolomide (TMZ) resistance in glioblastoma by inhibiting ferroptosis via the CHMP4B/GPX4 pathway. Targeting KIF4A may improve glioblastoma treatment outcomes.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis.
- Temozolomide (TMZ) is the standard first-line chemotherapy, but resistance limits its efficacy.
- The molecular mechanisms underlying TMZ resistance in GBM remain incompletely understood.
Purpose of the Study:
- To investigate the role of KIF4A in temozolomide (TMZ) resistance in glioblastoma (GBM).
- To elucidate the molecular mechanisms by which KIF4A influences GBM chemoresistance.
- To explore KIF4A as a potential therapeutic target for overcoming TMZ resistance in GBM.
Main Methods:
- Assessed ferroptosis levels using ROS, MDA, JC-1, and Western blot.
- Evaluated TMZ resistance via CCK8, cell cloning, and cell cycle analysis.
- Identified KIF4A downstream targets using protein profiling and immunofluorescence.
Main Results:
- KIF4A was found to inhibit ferroptosis in GBM cells through the CHMP4B/GPX4 axis, promoting TMZ resistance.
- Knockdown of KIF4A or CHMP4B sensitized GBM cells to TMZ chemotherapy.
- KIF4A also induced epithelial-mesenchymal transition, further enhancing TMZ resistance.
Conclusions:
- KIF4A plays a critical role in promoting TMZ resistance in glioblastoma by modulating ferroptosis and inducing EMT.
- The KIF4A-CHMP4B-GPX4 axis represents a novel mechanism of chemoresistance in GBM.
- Targeting KIF4A presents a promising therapeutic strategy for overcoming TMZ resistance in glioblastoma patients.
