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采用蛋白质组整体可溶性变化方法探索强心苷的抗癌机制。

Exploring the anticancer mechanism of cardiac glycosides using proteome integral solubility alteration approach.

机构信息

Department of Pharmacy, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, China.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.

出版信息

Cancer Med. 2024 Sep;13(18):e70252. doi: 10.1002/cam4.70252.

DOI:10.1002/cam4.70252
PMID:39350574
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11442762/
Abstract

BACKGROUND AND AIMS

Cardiac glycosides (CGs), traditionally used for heart failure, have shown potential as anti-cancer agents. This study aims to explore their multifaceted mechanisms in cancer cell biology using proteome integral solubility alteration (PISA), focusing on the interaction with key proteins implicated in cellular metabolism and mitochondrial function.

METHODS

We conducted lysate-based and intact-cell PISA assays on cancer cells treated with CGs (Digoxin, Digitoxin, Ouabain) to analyze protein solubility changes. This was followed by mass spectrometric analysis and bioinformatics to identify differentially soluble proteins (DSPs). Molecular docking simulations were performed to predict protein-CG interactions. Public data including gene expression changes upon CG treatment were re-analyzed for validation.

RESULTS

The PISA assays revealed CGs' broad-spectrum interactions, particularly affecting proteins like PKM2, ANXA2, SLC16A1, GOT2 and GLUD1. Molecular docking confirmed stable interactions between CGs and these DSPs. Re-analysis of public data supported the impact of CGs on cancer metabolism and cell signaling pathways.

CONCLUSION

Our findings suggest that CGs could be repurposed for cancer therapy by modulating cellular processes. The PISA data provide insights into the polypharmacological effects of CGs, warranting further exploration of their mechanisms and clinical potential.

摘要

背景和目的

传统上用于心力衰竭的强心苷（CGs）已显示出作为抗癌剂的潜力。本研究旨在使用整体蛋白质可溶性改变分析（PISA）探索其在癌症细胞生物学中的多方面机制，重点研究与细胞代谢和线粒体功能相关的关键蛋白的相互作用。

方法

我们对用 CG（地高辛、洋地黄毒苷、哇巴因）处理的癌细胞进行基于裂解物和完整细胞的 PISA 测定，以分析蛋白质可溶性变化。随后进行质谱分析和生物信息学分析以鉴定差异可溶性蛋白（DSP）。进行分子对接模拟以预测蛋白-CG 相互作用。对 CG 处理后基因表达变化的公共数据进行重新分析以验证。

结果

PISA 测定显示 CG 具有广谱相互作用，特别是影响 PKM2、ANXA2、SLC16A1、GOT2 和 GLUD1 等蛋白。分子对接证实 CG 与这些 DSP 之间存在稳定的相互作用。对公共数据的重新分析支持 CG 对癌症代谢和细胞信号通路的影响。

结论

我们的研究结果表明，通过调节细胞过程，CG 可被重新用于癌症治疗。PISA 数据提供了 CG 多药理学作用的见解，值得进一步探索其机制和临床潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/c1f255efd262/CAM4-13-e70252-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/d314f024b231/CAM4-13-e70252-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/1df84f6e0fa7/CAM4-13-e70252-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/dfc63af46d69/CAM4-13-e70252-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/2688c5b5dde9/CAM4-13-e70252-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/fc6f0868056e/CAM4-13-e70252-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/ce793425ebb0/CAM4-13-e70252-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/c1f255efd262/CAM4-13-e70252-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/d314f024b231/CAM4-13-e70252-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/1df84f6e0fa7/CAM4-13-e70252-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/dfc63af46d69/CAM4-13-e70252-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/2688c5b5dde9/CAM4-13-e70252-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/fc6f0868056e/CAM4-13-e70252-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/ce793425ebb0/CAM4-13-e70252-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61c/11442762/c1f255efd262/CAM4-13-e70252-g007.jpg

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引用本文的文献

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Correction to "Exploring the Anticancer Mechanism of Cardiac Glycosides Using Proteome Integral Solubility Alteration Approach".对《使用蛋白质组整体溶解度改变方法探索强心苷的抗癌机制》的勘误
Cancer Med. 2024 Nov;13(21):e70381. doi: 10.1002/cam4.70381.

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