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异常激活的Notch1通过破坏小鼠线粒体功能来促进由雄激素信号驱动的前列腺扩大

Jin-Wen Kang¹, Jia-Peng He¹, Ying-Nan Liu¹

¹College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China.

Cellular and molecular life sciences : CMLS

|March 28, 2024

概括

过度激活的Notch1信号会增加雄激素受体的敏感性并破坏线粒体功能,从而导致前列腺扩大. 用N-乙-L-氨酸 (NAC) 进行抗氧化疗法有效地逆转这些变化,为良性前列腺增生 (BPH) 提供了潜在的治疗方法.

科学领域:

泌尿器科泌尿器科泌尿器科泌尿器科
分子生物学分子生物学
细胞生物学细胞生物学

背景情况:

像良性前列腺增生症 (BPH) 和前列腺癌 (PCa) 这样的前列腺疾病在全球范围内正在增加,特别是在老年人群中.
诺奇信号通路对于前列腺发育至关重要,但其在前列腺扩大中的作用尚不清楚.

研究的目的:

研究Notch1信号过激活在前列腺扩大和前列腺增生中的作用.
阐明Notch1诱导的前列腺变化背后的分子机制.
评估抗氧化剂治疗在减轻这些影响方面的治疗潜力.

主要方法:

在小鼠前列腺上皮细胞 (OEx) 中,Notch1信号的过度激活.
对雄激素受体 (AR) 表达和对雄激素 (DHT) 敏感性的分析.
评估线粒体数量,功能和活性氧物种 (ROS) 水平.
对N-乙-L-氨酸 (NAC) 治疗疗效的评估.
对人类BPH患者数据 (scRNA-seq) 和小鼠原生细胞种群的分析.

主要成果:

在小鼠前列腺上皮细胞中,Notch1信号过度激活导致前列腺通过增强细胞增殖和抑制细胞亡而扩大.
诺奇1信号直接调节了雄激素受体 (AR),增加了前列腺对雄激素的敏感性.
在OEx小鼠中观察到线粒体功能障碍和活性氧物种 (ROS) 的增加.
抗氧化剂N-乙-L-氨酸 (NAC) 治疗显著缓解了前列腺激增.
在人类BPH和OEx小鼠中发现了增加的Notch信号活动和原始细胞群 (TROP2+,Club细胞).

结论:

过度激活的Notch1信号诱导前列腺扩大通过增加AR敏感性,破坏线粒体代谢,ROS升高,以及更多的原始细胞.
通过NAC治疗,可以扭转Notch1介导的前列腺增生症.
这些发现凸显了Notch信号作为前列腺疾病的关键调节器,并建议抗氧化疗法作为可行的治疗策略.

关键词:

在 DHT 中,DHT 是 DHT.鼠标鼠标是一个鼠标.这是Notch1信号.前列腺扩大前列腺扩大这就是ROSOS ROS.

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