International journal of radiation biology · 2025
POT1-AS1/IGF2BP2/GPX4 promotes temozolomide resistance and radioresistance in glioblastoma by inhibiting ferroptosis.
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Dong Qiufeng, Huo Junli, Yan Zhifeng, Li Juan, Chen Xiaoyan, Li Liwen, Zhen Haining
Аннотация
AIM: Glioblastoma (GBM) is an aggressive brain tumor characterized by resistance to temozolomide (TMZ) and radiotherapy. This study investigates the role of long non-coding RNA POT1-AS1 in modulating TMZ resistance (TMZR) and radiation-resistant (RR) in GBM by regulating ferroptosis via the IGF2BP2/glutathione peroxidase 4 (GPX4) pathway.
METHODS: Human GBM cell lines, including TMZR and RR variants, were analyzed. POT1-AS1 expression was silenced using shRNA in U-87MG RR and U-87MG TMZR cells. The impact of POT1-AS1 knockdown on ferroptosis was evaluated by measuring iron concentration, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels. GPX4 protein expression was also analyzed. Ferroptosis inhibition experiments were conducted using Fer-1. The stability of GPX4 mRNA was assessed by RNA immunoprecipitation (RIP) assays.
RESULTS: POT1-AS1 and GPX4 were significantly overexpressed in U-87MG RR and TMZR cells. Knockdown of POT1-AS1 increased ferroptosis markers, including elevated iron and ROS levels, reduced GSH content, and downregulated GPX4 expression. POT1-AS1 knockdown sensitized GBM cells to TMZ and radiation. Additionally, the ferroptosis inhibitor Fer-1 reversed the effects of POT1-AS1 knockdown. RIP assays confirmed the interaction between POT1-AS1, IGF2BP2, and GPX4 mRNA, highlighting the POT1-AS1/IGF2BP2/GPX4 axis as a key regulator of ferroptosis.
CONCLUSIONS: POT1-AS1 promotes TMZ and radiation resistance in GBM by regulating ferroptosis through the IGF2BP2/GPX4 axis. Targeting this pathway may offer a new therapeutic strategy for overcoming GBM treatment resistance.
METHODS: Human GBM cell lines, including TMZR and RR variants, were analyzed. POT1-AS1 expression was silenced using shRNA in U-87MG RR and U-87MG TMZR cells. The impact of POT1-AS1 knockdown on ferroptosis was evaluated by measuring iron concentration, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels. GPX4 protein expression was also analyzed. Ferroptosis inhibition experiments were conducted using Fer-1. The stability of GPX4 mRNA was assessed by RNA immunoprecipitation (RIP) assays.
RESULTS: POT1-AS1 and GPX4 were significantly overexpressed in U-87MG RR and TMZR cells. Knockdown of POT1-AS1 increased ferroptosis markers, including elevated iron and ROS levels, reduced GSH content, and downregulated GPX4 expression. POT1-AS1 knockdown sensitized GBM cells to TMZ and radiation. Additionally, the ferroptosis inhibitor Fer-1 reversed the effects of POT1-AS1 knockdown. RIP assays confirmed the interaction between POT1-AS1, IGF2BP2, and GPX4 mRNA, highlighting the POT1-AS1/IGF2BP2/GPX4 axis as a key regulator of ferroptosis.
CONCLUSIONS: POT1-AS1 promotes TMZ and radiation resistance in GBM by regulating ferroptosis through the IGF2BP2/GPX4 axis. Targeting this pathway may offer a new therapeutic strategy for overcoming GBM treatment resistance.