UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2020-02-22

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Cell Biology | Cells | Enzymes and Coenzymes | Molecular Biology | Neoplasms | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

Glioblastoma multiforme (GBM) is an aggressive adult brain tumour with poor prognosis. Roles for peptidylarginine deiminases (PADs) in GBM have recently been highlighted. Here, two GBM cell lines were treated with PAD2, PAD3 and PAD4 isozyme-specific inhibitors. Effects were assessed on extracellular vesicle (EV) signatures, including EV-microRNA cargo (miR21, miR126 and miR210), and on changes in cellular protein expression relevant for mitochondrial housekeeping (prohibitin (PHB)) and cancer progression (stromal interaction molecule 1 (STIM-1) and moesin), as well as assessing cell invasion. Overall, GBM cell-line specific differences for the three PAD isozyme-specific inhibitors were observed on modulation of EV-signatures, PHB, STIM-1 and moesin protein levels, as well as on cell invasion. The PAD3 inhibitor was most effective in modulating EVs to anti-oncogenic signatures (reduced miR21 and miR210, and elevated miR126), to reduce cell invasion and to modulate protein expression of pro-GBM proteins in LN229 cells, while the PAD2 and PAD4 inhibitors were more effective in LN18 cells. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for deiminated proteins relating to cancer, metabolism and inflammation differed between the two GBM cell lines. Our findings highlight roles for the different PAD isozymes in the heterogeneity of GBM tumours and the potential for tailored PAD-isozyme specific treatment.

Keywords

HIF-1, Stromal interaction molecule 1 (STIM-1), extracellular vesicles (EVs), glioblastoma multiforme (GBM), microRNA (miR21, miR126, miR210), moesin, peptidylarginine deiminases (PADs), prohibitin (PHB), protein deimination

Rights and Permissions

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.3390/ijms21041495

Source

Uysal-Onganer P, MacLatchy A, Mahmoud R, Kraev I, Thompson PR, Inal JM, Lange S. Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines. Int J Mol Sci. 2020 Feb 22;21(4):1495. doi: 10.3390/ijms21041495. PMID: 32098295. Link to article on publisher's site

Journal/Book/Conference Title

International journal of molecular sciences

Related Resources

Link to Article in PubMed

PubMed ID

32098295

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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