.png){kind=icon}
.png){kind=icon}
Return
ELK3‑driven MRP1 upregulation promotes vesicle‑associated drug efflux and chemoresistance in GBM
.png){kind=icon}
OA
AI
Y
J
Q
J
Y
X
X
X
L
DOI：10.1007/s12672-026-05730-6.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Temozolomide (TMZ) resistance is a major clinical challenge in glioblastoma (GBM) treatment, yet its underlying mechanisms remain poorly understood. This study aimed to investigate the role and mechanism of the transcription factor ELK3 in TMZ resistance. ELK3 expression in recurrent GBM and TMZ-resistant cells was examined via IHC and Western blot. Its functional role in TMZ resistance was validated through gain/loss-of-function experiments assessing viability, apoptosis, and DNA damage. Mechanistic studies utilized methodologies including chromatin immunoprecipitation, luciferase reporter assays, and bioinformatics analyses. The ELK3/ABCC1 axis in drug efflux was investigated by evaluating vesicle formation via scanning and transmission electron microscopy and measuring intracellular TMZ via HPLC. Therapeutic efficacy was assessed in an intracranial mouse model. ELK3 was upregulated in recurrent GBM and TMZ-resistant cells. Overexpression conferred TMZ resistance, reducing DNA damage/apoptosis, while knockdown restored sensitivity. Mechanistically, ELK3 upregulated ABCC1 (MRP1) at the transcriptional level. High ABCC1 correlated with poor prognosis in patients. Under TMZ pressure, ELK3-driven MRP1 promoted vesicle-associated drug efflux, lowering intracellular TMZ. In vivo, ELK3 knockdown combined with TMZ synergistically inhibited resistant tumors and prolonged survival. This study reveals a novel mechanism by which the ELK3/ABCC1 axis drives TMZ resistance through regulating vesicle-associated drug efflux, providing a potential therapeutic target for overcoming chemoresistance in GBM.
Keywords:
Glioma
TMZ
Resistance
ELK3
Vesicle-associated drug efflux
Journal
IF:
2.9
Papers:
3.5K
Citations:
1.6K
Organization
Cited Papers