泰莫佐洛米德通过通过HIF1α/HIF2α调节,通过与衰老相关的重编程促进质母细胞瘤茎的表达
Pan Wang1, Bin Liao1, Sheng Gong1
1Department of Neurosurgery, Chongqing Research Center for Glioma Precision Medicine, Chongqing General Hospital, Chongqing University, Chongqing, China.
Cell death & disease
|April 19, 2025
概括
在多形质母细胞瘤 (glioblastoma multiforme) 中,泰莫佐洛米德治疗可以通过诱导细胞衰老和干性,由HIF1α/HIF2α通路驱动,矛盾地增加瘤恶性病变. 抑制这些途径可能会改善质母细胞瘤治疗结果.
科学领域:
- 神经瘤学神经瘤学
- 癌症生物学 癌症生物学
- 细胞衰老 细胞衰老
背景情况:
- 在temozolomide (TMZ) 治疗后,多形质母细胞瘤 (GBM) 复发呈现出恶性,侵入性和茎状性增加.
- 驱动GBM复发和TMZ后恶性瘤增强的机制仍然不完全理解.
- 治疗TMZ可以诱导GBM细胞的一个子集进入细胞循环停止并采用与衰老相关的分泌表型 (SASP).
研究的目的:
- 阐明TMZ治疗有助于增强复发性GBM的干性和恶性病变的机制.
- 调查细胞衰老和缺氧诱导因素 (HIF) 在TMZ诱导的GBM复发中的作用.
- 确定潜在的治疗目标,以克服TMZ在GBM中的耐药性.
主要方法:
- 利用基因组丰富分析 (GSEA) 和miRNA和mRNA序列上的KEGG通路分析.
- 研究了在TMZ治疗期间和之后在GBM细胞中HIF1α和HIF2α的表达和作用.
- 在暴露于TMZ的GBM细胞中进行了HIF1α和HIF2α淘汰试验,以评估对衰老和干状聚合物形成的影响.
主要成果:
- 治疗TMZ诱导GBM细胞进入衰老,激活SASP,并最终形成干状聚合物,具有增加的侵入性和化疗耐药性.
- GSEA和KEGG分析显示,标志性缺氧和HIF1信号通路的激活.
- 淘汰HIF1α和HIF2α显著降低了TMZ治疗的GBM细胞中衰老细胞的形成和干状聚合物的发展.
结论:
- 通过诱导细胞衰老和激活HIF信号通路,TMZ疗法可以无意中促进GBM复发和恶性瘤增加.
- 在TMZ治疗后,HIF1α和HIF2α在衰老细胞和干状聚合物的发展中起着关键的调节作用.
- 向衰老细胞形成和抑制HIF1α/HIF2α表达是改善复发性GBM治疗结果的有希望的策略.
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