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RSK3 切换细胞命运:从压力诱导的衰老到恶性进展
Anda Huna1,2, Jean-Michel Flaman1,2, Catalina Lodillinsky3,4
1Cancer Research Center of Lyon, Inserm U1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard, 69373, Lyon, France.
Journal of experimental & clinical cancer research : CR
|November 26, 2023
概括
核糖体S6激酶3 (RSK3) 通过抑制NF-κB通路来防止TGFβ诱导的衰老. 在乳腺癌中,RSK3促进表皮-介质细胞过渡 (EMT) 和入侵,将细胞从衰老转变为恶性.
科学领域:
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
- 分子信号传输的方法
背景情况:
- 转化生长因子β (TGFβ) 在上皮细胞中诱导衰老和上皮-介质细胞过渡 (EMT).
- 在癌症期间,细胞经常逃避TGFβ诱导的衰老,同时保持EMT,促进瘤的进展.
- 在TGFβ诱导的衰老逃逸背后的机制尚未完全理解.
研究的目的:
- 确定使细胞能够逃避TGFβ诱导的衰老的分子机制.
- 研究特定激酶在调节衰老和EMT之间的平衡中的作用.
- 探索这些发现对乳腺癌发展和进展的影响.
主要方法:
- 使用原始人类乳腺上皮细胞 (HMEC) 和永生细胞系的体外研究.
- 基因酶库查,基因表达分析 (RNA微阵列,RT-qPCR) 和蛋白质分析 (西方斑,免疫光).
- 衰老测定,免疫沉,质谱,蛋白酶体活动测定,数据库分析 (METABRIC) 和小鼠异种移植模型.
主要成果:
- 确定了氨酸/氨酸激酶RSK3 (RPS6KA2) 作为一个关键调节器,可以逆转TGFβ诱导的衰老.
- RSK3表达被TGFβ以SMAD3依赖的方式下调,其下降有助于衰老.
- RSK3通过减少蛋白质酶介导的IκBα降解,促进EMT和入侵,并增强体内瘤形成来抑制NF-κB通路.
结论:
- RSK3充当关键开关,指导细胞命运从衰老向恶性瘤,以响应TGFβ信号传递.
- 这些发现突出了RSK3在促进EMT和入侵中的作用,将衰老逃避与乳腺癌恶性进展联系起来.
- 在人类乳腺癌中,RSK3的表达与瘤的攻击性特征相关,这表明它有可能成为治疗点.
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