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Open AccessArticle

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

1
Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
2
School of Life Sciences, University of Westminster, London W1W 6UW, UK
3
Electron Microscopy Suite, Faculty of Science, Technology, Engineering and Mathematics, Open University, Milton Keynes MK7 6AA, UK
4
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
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School of Human Sciences, London Metropolitan University, London N7 8DB, UK
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Tissue Architecture and Regeneration Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1495; https://doi.org/10.3390/ijms21041495
Received: 27 January 2020 / Revised: 13 February 2020 / Accepted: 20 February 2020 / Published: 22 February 2020
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. View Full-Text
Keywords: peptidylarginine deiminases (PADs); protein deimination; extracellular vesicles (EVs); glioblastoma multiforme (GBM); prohibitin (PHB); Stromal interaction molecule 1 (STIM-1); moesin; microRNA (miR21, miR126, miR210); HIF-1 peptidylarginine deiminases (PADs); protein deimination; extracellular vesicles (EVs); glioblastoma multiforme (GBM); prohibitin (PHB); Stromal interaction molecule 1 (STIM-1); moesin; microRNA (miR21, miR126, miR210); HIF-1
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Uysal-Onganer, P.; MacLatchy, A.; Mahmoud, R.; Kraev, I.; Thompson, P.R.; Inal, J.M.; 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, 21, 1495.

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