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细胞衰老和炎症反应中的基因毒性压力和STING激活之间的相互作用
Anshurekha Dash1, Akshay S Kulkarni2, Faisal Irshad1
1Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India.
International immunopharmacology
|August 21, 2025
概括
通过独立于cGAS的STING通路激活,Peharmaline类似物NDS101781会触发乳腺癌细胞衰老. 这种基因毒性分子在体内有望抑制瘤生长.
科学领域:
- 癌症学
- 免疫学
- 细胞生物学
背景情况:
- 通过DNA损伤激活的STING (干扰素基因刺激器) 途径对先天免疫至关重要.
- 细胞衰老是一种不可逆转的生长停止状态,对癌症治疗有影响.
研究的目的:
- 研究Peharmaline模拟物NDS101781诱导细胞衰老的机制.
- 探索STING途径在NDS101781中介衰老中的作用.
- 在临床前乳腺癌模型中评估NDS101781的抗瘤功效.
主要方法:
- 使用NDS101781治疗乳腺癌细胞.
- 对DNA损伤反应 (DDR) 标记和衰老特征的分析.
- 使用siRNA对TMEM173 (STING) 的STING通路激活的研究.
- 评估ATM,p53,cGAS和下游的信号分子.
- 在4T1- p53乳腺癌模型中进行的药理动力学研究和体内瘤生长抑制试验.
主要成果:
- 在乳腺癌细胞中,NDS101781诱导了DNA损伤反应和衰老特征.
- 在独立于cGAS的NDS101781中介衰老中,STING激活是必不可少的.
- ATM和p53在非正规的STING激活级联中发挥了关键作用.
- 在体内,NDS101781表现出有利的药理动力学和显著抑制瘤生长.
- 在某些条件下,p21发挥了双重作用,调解衰老,但延迟了亡.
结论:
- NDS101781是一种强烈的基因毒剂,通过cGAS独立的ATM/ p53调节的STING激活途径诱导衰老.
- 在临床前的乳腺癌模型中,NDS101781表现出有前途的抗瘤活性.
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