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消除多塞素诱导的衰老减弱了RB1缺乏CRPC的恶性进展

Huilan Su¹, Liqun Huang², Wenwen Xia³

¹Research Center for Translational Medicine, Cancer Stem Cell Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.

Cellular oncology (Dordrecht, Netherlands)

|November 11, 2025

概括

多西素诱导的衰老 (DIS) 通过促进转移和治疗耐药性来加速RB1-缺乏前列腺癌 (PCa) 的进展. 衰老剂ABT-263通过向IL-20通路来消除衰老细胞并恢复dcetaxel的敏感性.

科学领域:

在瘤学瘤学.
癌症生物学癌症生物学
分子医学是分子医学.

背景情况:

视网膜细胞瘤L (RB1) 突变是晚期前列腺癌 (PCa) 的晚期事件,与复发和治疗耐药性有关.
治疗诱导的衰老 (TIS) 可能会促进转移,但RB1-缺陷割抵抗性前列腺癌 (CRPC) 中的多西素诱导衰老 (DIS) 的机制尚不清楚.

研究的目的:

调查DIS在RB1缺乏CRPC中的作用.
揭示DIS促进恶性瘤和治疗耐药性的机制.
评估针对RB1缺乏CRPC中的DIS的治疗策略.

主要方法:

使用TCGA-PRAD数据和临床样本对RB1表达和瘤恶性病的系统评估.
建立多个CRPC模型 (小鼠和人类) 来研究RB1缺陷和对照细胞中的DIS.
RNA测序以确定shRB1-DIS细胞中的瘤性SASP因子;使用免疫光学,流细胞计,ChIP,双光酶记者测定和分子对接来研究分子机制.

主要成果:

人类PCa.中的RB1表达与恶性瘤有负相关性.
在RB1缺陷模型中,DIS促进转移并加速向神经内分泌PC (NEPC) 的过渡,其特征是SA-β-gal,p27^Kip和特定的SASP因子 (IL-1α,CCL5,CCL20,MMP3,IL-20) 的升高.
一个新的FOXA1-IL20-IL20Rβ轴驱动M2类巨细胞两极分化,有助于攻击性和多塞抗性. ABT-263消除了shRB1-DIS细胞和SASP (特别是IL-20),抑制了M2巨细胞,降低了攻击性,并恢复了多塞素敏感性.

结论:

DIS通过瘤原性SASP,特别是IL-20加速了RB1缺乏CRPC的恶性进展.
已识别的FOXA1-IL-20-IL20Rβ轴驱动M2巨细胞两极分化,促进瘤的攻击性和多塞素抵抗性.
衰老剂ABT-263选择性地消除衰老细胞,抑制SASP (IL-20),并恢复RB1缺乏CRPC中的多塞塔克塞尔敏感性,提供了一种新的治疗策略.

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