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Stat5 诱导前列腺癌细胞中的雄激素受体（AR）基因转录，并为靶向 AR 信号通路提供了一个可药物干预的途径。

Stat5 induces androgen receptor () gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.

机构信息

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.

出版信息

Sci Adv. 2024 Mar;10(9):eadi2742. doi: 10.1126/sciadv.adi2742. Epub 2024 Feb 28.

DOI:10.1126/sciadv.adi2742
PMID:38416822
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10901378/
Abstract

Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of gene transcription. Stat5 suppression inhibited gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, and truncated AR proteins. Pharmacological Stat5 inhibition by a specific small-molecule Stat5 inhibitor down-regulated Stat5-inducible genes as well as AR and AR-regulated genes and suppressed PC growth. This work introduces the concept of Stat5 as an inducer of gene transcription in PC. Pharmacological Stat5 inhibitors may represent a new strategy for suppressing AR and CRPC growth.

摘要

雄激素受体（AR）驱动前列腺癌（PC）的生长和进展，靶向 AR 信号转导是 PC 药物治疗的主要方法。由于 AR 活性的恢复，耐药性相对较快地产生。该领域的一个主要空白是缺乏对可靶向机制的理解，这些机制会导致去势抵抗性 PC（CRPC）中持续的 AR 表达。本研究揭示了活跃的 Stat5 信号的一个意想不到的功能，Stat5 是已知的 PC 生长和临床进展的促进剂，它是转录的有力诱导物。Stat5 抑制在临床前 PC 模型中抑制基因转录，并降低野生型、突变型和截断型 AR 蛋白的水平。通过特异性小分子 Stat5 抑制剂抑制 Stat5 诱导的基因以及 AR 和 AR 调节的基因，并抑制 PC 生长，从而抑制 Stat5 的药理学抑制。这项工作介绍了 Stat5 在 PC 基因转录中的诱导作用的概念。药理学 Stat5 抑制剂可能代表抑制 AR 和 CRPC 生长的新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/dd17576f226f/sciadv.adi2742-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/7332aa34c1e6/sciadv.adi2742-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/88a680d8b863/sciadv.adi2742-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/ed0dde2ca5df/sciadv.adi2742-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/73506dfe63ab/sciadv.adi2742-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/26bc12bbe100/sciadv.adi2742-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/46982648b139/sciadv.adi2742-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/ae9973d14bab/sciadv.adi2742-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/1442bd7901bc/sciadv.adi2742-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/8d6392a887fa/sciadv.adi2742-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/dd17576f226f/sciadv.adi2742-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/7332aa34c1e6/sciadv.adi2742-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/88a680d8b863/sciadv.adi2742-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/ed0dde2ca5df/sciadv.adi2742-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/73506dfe63ab/sciadv.adi2742-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/26bc12bbe100/sciadv.adi2742-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/46982648b139/sciadv.adi2742-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/ae9973d14bab/sciadv.adi2742-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/1442bd7901bc/sciadv.adi2742-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/8d6392a887fa/sciadv.adi2742-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7520/10901378/dd17576f226f/sciadv.adi2742-f10.jpg

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