STAT3/LKB1通过调节mTORC1/CREB通路来控制转移性前列腺癌
Jan Pencik1,2,3,4, Cecile Philippe5, Michaela Schlederer6
1Department of Pathology, Medical University of Vienna, 1090, Vienna, Austria. jpencik@salk.edu.
Molecular cancer
|August 12, 2023
概括
失去STAT3基因与致命的前列腺癌 (PCa) 和转移有关. 一种糖尿病药物梅特福明通过向STAT3/mTORC1/CREB通路,在治疗PCa方面表现有前途,提供了一种新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 前列腺癌 (PCa) 是男性癌症死亡的主要原因,转移性PCa (mPCa) 是致死率的主要驱动因素.
- 尚不完全了解mPCa进展的潜在机制.
- 在mPCa中,PTEN基因缺失很常见,在液体活检中经常观察到它与STAT3的共同缺失.
研究的目的:
- 研究STAT3在转移性前列腺癌的发展和进展中的作用.
- 探索甲胺在针对mPCa治疗中针对STAT3信号通路的治疗潜力.
主要方法:
- 在mPCa患者液体活检中对PTEN和STAT3的基因组共删除的分析.
- 使用Pten-null小鼠前列腺模型研究Stat3损失对转移的影响.
- 用甲胺治疗表达STAT3/AR的PCa异位移植和PCa患者.
- 评估分子变化,包括LKB1/pAMPK,mTORC1/CREB,AR和PSA水平.
主要成果:
- 在Pten-null小鼠模型中,Stat3的丧失通过降低LKB1/pAMPK和激活mTOR/CREB促进了转移.
- 构成性Stat3的激活抑制了mTORC1/CREB,并阻止了mPCa.
- 甲胺治疗减少了PCa外移植中的瘤生长,mTORC1/CREB,AR和PSA水平.
- 在高格里森等级和2型糖尿病的PCa患者中,甲胺上调STAT3和降低mTORC1.
- 高CREB表达与更差的临床结果以及PCa复发和转移的风险增加相关.
结论:
- 通过LKB1/pAMPK/mTORC1/CREB信号通路,STAT3在控制转移性前列腺癌进展方面发挥着至关重要的作用.
- 用甲福明准这种途径代表了致命mPCa.的有前途的新疗法策略.
- STAT3和CREB是预测PCa结果和治疗反应的潜在生物标志物.
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