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靶向波形蛋白的药物ALD-R491可部分逆转肺癌细胞的上皮-间质转化及波形蛋白相互作用组。

The Vimentin-Targeting Drug ALD-R491 Partially Reverts the Epithelial-to-Mesenchymal Transition and Vimentin Interactome of Lung Cancer Cells.

作者信息

Rosier Marieke, Krstulović Anja, Kim Hyejeong Rosemary, Kaur Nihardeep, Enakireru Erhumuoghene Mary, Symmes Deebie, Dobra Katalin, Chen Ruihuan, Evans Caroline A, Gad Annica K B

机构信息

Department of Oncology-Pathology, Karolinska Institutet, 171 64 Solna, Sweden.

Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, UK.

出版信息

Cancers (Basel). 2024 Dec 30;17(1):81. doi: 10.3390/cancers17010081.

DOI:10.3390/cancers17010081
PMID:39796712
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11720119/
Abstract

The epithelial-to-mesenchymal transition (EMT) is a common feature in early cancer invasion. Increased vimentin is a canonical marker of the EMT; however, the role of vimentin in EMT remains unknown. To clarify this, we induced EMT in lung cancer cells with TGF-β1, followed by treatment with the vimentin-targeting drug ALD-R491, live-cell imaging, and quantitative proteomics. We identified 838 proteins in the intermediate filament fraction of cells. TGF-β1 treatment increased the proportion of vimentin in this fraction and the levels of 24 proteins. Variants of fibronectin showed the most pronounced increase (137-fold), followed by regulators of the cytoskeleton, cell motility, and division, such as the mRNA-splicing protein SON. TGF-β1 increased cell spreading and cell migration speed, and changed a positive correlation between cell migration speed and persistence to negative. ALD-R491 reversed these mesenchymal phenotypes to epithelial and the binding of RNA-binding proteins, including SON. These findings present many new interactors of intermediate filaments, describe how EMT and vimentin filament dynamics influence the intermediate filament interactome, and present ALD-R491 as a possible EMT-inhibitor. The observations support the hypothesis that the dynamic turnover of vimentin filaments and their interacting proteins govern mesenchymal cell migration, EMT, cell invasion, and cancer metastasis.

摘要

上皮-间质转化（EMT）是早期癌症侵袭的一个常见特征。波形蛋白表达增加是EMT的一个典型标志物；然而，波形蛋白在EMT中的作用仍不清楚。为了阐明这一点，我们用转化生长因子-β1（TGF-β1）诱导肺癌细胞发生EMT，随后用靶向波形蛋白的药物ALD-R491进行处理，并进行活细胞成像和定量蛋白质组学分析。我们在细胞的中间丝组分中鉴定出838种蛋白质。TGF-β1处理增加了该组分中波形蛋白的比例以及24种蛋白质的水平。纤连蛋白的变体显示出最显著的增加（137倍），其次是细胞骨架、细胞运动和分裂的调节因子，如mRNA剪接蛋白SON。TGF-β1增加了细胞铺展和细胞迁移速度，并将细胞迁移速度与持续性之间的正相关转变为负相关。ALD-R491将这些间充质表型逆转为上皮表型，并逆转了包括SON在内的RNA结合蛋白的结合。这些发现揭示了许多新的中间丝相互作用蛋白，描述了EMT和波形蛋白丝动力学如何影响中间丝相互作用组，并表明ALD-R491可能是一种EMT抑制剂。这些观察结果支持了这样一种假说，即波形蛋白丝及其相互作用蛋白的动态更新控制着间充质细胞迁移、EMT、细胞侵袭和癌症转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/02715e650ae3/cancers-17-00081-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/f34634620169/cancers-17-00081-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/aca6d4461b63/cancers-17-00081-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/160e6df1105b/cancers-17-00081-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/37e780971d91/cancers-17-00081-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/02715e650ae3/cancers-17-00081-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/f34634620169/cancers-17-00081-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/aca6d4461b63/cancers-17-00081-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/160e6df1105b/cancers-17-00081-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/37e780971d91/cancers-17-00081-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecf8/11720119/02715e650ae3/cancers-17-00081-g005.jpg

相似文献

[1]
The Vimentin-Targeting Drug ALD-R491 Partially Reverts the Epithelial-to-Mesenchymal Transition and Vimentin Interactome of Lung Cancer Cells.

Cancers (Basel). 2024-12-30

[2]
ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality.

Front Cell Dev Biol. 2022-11-22

[3]
Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance.

Toxicology. 2014-8-1

[4]
Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metastasis.

Toxicology. 2012-11-9

[5]
Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice.

Biomed Pharmacother. 2023-12

[6]
Interaction of hnRNP K with MAP 1B-LC1 promotes TGF-β1-mediated epithelial to mesenchymal transition in lung cancer cells.

BMC Cancer. 2019-9-6

[7]
Geraniin inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration, invasion and anoikis resistance.

Bioorg Med Chem Lett. 2015-9-1

[8]
Transforming growth factor-β1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition.

Mol Cell Biochem. 2011-6-22

[9]
TGF-β1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line, leading to an increase of migration ability in the CD133+ A549 cell fraction.

Cell Death Dis. 2013-5-2

[10]
Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion.

Bioorg Med Chem Lett. 2017-8-1

本文引用的文献

[1]
Vimentin-mediated buffering of internal integrin β1 pool increases survival of cells from anoikis.

BMC Biol. 2024-6-24

[2]
TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination.

Transl Gastroenterol Hepatol. 2024-1-25

[3]
Vimentin at the core of wound healing.

Trends Cell Biol. 2024-3

[4]
"Beyond transcription: How post-transcriptional mechanisms drive neural crest EMT".

Genesis. 2024-2

[5]
Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer.

Oncogenesis. 2023-8-12

[6]
Vimentin is required for tumor progression and metastasis in a mouse model of non-small cell lung cancer.

Oncogene. 2023-6

[7]
The Role of the Ectopeptidase APN/CD13 in Cancer.

Biomedicines. 2023-2-28

[8]
ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality.

Front Cell Dev Biol. 2022-11-22

[9]
Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer.

Cancers (Basel). 2022-7-14

[10]
Roles of vimentin in health and disease.

Genes Dev. 2022-4-1

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