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神经肽诱导的蛋白酶体活性上调先于核因子 κB 在雄激素非依赖性前列腺癌细胞中的激活。

Neuropeptide-inducible upregulation of proteasome activity precedes nuclear factor kappa B activation in androgen-independent prostate cancer cells.

机构信息

Department of Medical Oncology, University Hospital of Larissa, Larissa, Greece.

出版信息

Cancer Cell Int. 2012 Jun 20;12(1):31. doi: 10.1186/1475-2867-12-31.

DOI:10.1186/1475-2867-12-31
PMID:22715899
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3441896/
Abstract

BACKGROUND

Upregulation of nuclear factor kappa B (NFκB) activity and neuroendocrine differentiation are two mechanisms known to be involved in prostate cancer (PC) progression to castration resistance. We have observed that major components of these pathways, including NFκB, proteasome, neutral endopeptidase (NEP) and endothelin 1 (ET-1), exhibit an inverse and mirror image pattern in androgen-dependent (AD) and -independent (AI) states in vitro.

METHODS

We have now investigated for evidence of a direct mechanistic connection between these pathways with the use of immunocytochemistry (ICC), western blot analysis, electrophoretic mobility shift assay (EMSA) and proteasome activity assessment.

RESULTS

Neuropeptide (NP) stimulation induced nuclear translocation of NFκB in a dose-dependent manner in AI cells, also evident as reduced total inhibitor κB (IκB) levels and increased DNA binding in EMSA. These effects were preceded by increased 20 S proteasome activity at lower doses and at earlier times and were at least partially reversed under conditions of NP deprivation induced by specific NP receptor inhibitors, as well as NFκB, IκB kinase (IKK) and proteasome inhibitors. AD cells showed no appreciable nuclear translocation upon NP stimulation, with less intense DNA binding signal on EMSA.

CONCLUSIONS

Our results support evidence for a direct mechanistic connection between the NPs and NFκB/proteasome signaling pathways, with a distinct NP-induced profile in the more aggressive AI cancer state.

摘要

背景

核因子 kappa B（NFκB）活性的上调和神经内分泌分化是已知参与前列腺癌（PC）向去势抵抗进展的两种机制。我们已经观察到，这些途径的主要成分，包括 NFκB、蛋白酶体、中性内肽酶（NEP）和内皮素 1（ET-1），在体外依赖雄激素（AD）和非依赖雄激素（AI）状态下表现出相反和镜像的模式。

方法

我们现在使用免疫细胞化学（ICC）、western blot 分析、电泳迁移率变动分析（EMSA）和蛋白酶体活性评估，研究这些途径之间是否存在直接的机制联系的证据。

结果

神经肽（NP）刺激以剂量依赖性方式诱导 AI 细胞中 NFκB 的核易位，这也表现为总抑制剂 κB（IκB）水平降低和 EMSA 中 DNA 结合增加。这些效应之前是较低剂量和较早时间的 20S 蛋白酶体活性增加，并且在 NP 受体抑制剂、NFκB、IκB 激酶（IKK）和蛋白酶体抑制剂诱导的 NP 剥夺条件下至少部分逆转。AD 细胞在 NP 刺激下没有明显的核易位，EMSA 上的 DNA 结合信号较弱。

结论

我们的结果支持 NPs 和 NFκB/蛋白酶体信号通路之间存在直接机制联系的证据，在更具侵袭性的 AI 癌症状态下，存在独特的 NP 诱导谱。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/504814013301/1475-2867-12-31-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/a53615f434f6/1475-2867-12-31-1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/897371226e76/1475-2867-12-31-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/f01933eb67fe/1475-2867-12-31-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/d198bfec5e62/1475-2867-12-31-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/6a8745fba780/1475-2867-12-31-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/d62a29584293/1475-2867-12-31-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/504814013301/1475-2867-12-31-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/a53615f434f6/1475-2867-12-31-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/25eb9a30798b/1475-2867-12-31-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/897371226e76/1475-2867-12-31-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/f01933eb67fe/1475-2867-12-31-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/d198bfec5e62/1475-2867-12-31-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/6a8745fba780/1475-2867-12-31-6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca8/3441896/504814013301/1475-2867-12-31-8.jpg

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