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Article

Peptidylarginine Deiminases Post-Translationally Deiminate Prohibitin and Modulate Extracellular Vesicle Release and MicroRNAs in Glioblastoma Multiforme

1
Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, London N7 8DB, UK
2
Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
3
Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London W1W 6UW, UK
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School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
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Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Extracellular Vesicle Research Unit and Bioscience Research Group, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
7
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. 2019, 20(1), 103; https://doi.org/10.3390/ijms20010103
Received: 7 December 2018 / Revised: 22 December 2018 / Accepted: 25 December 2018 / Published: 28 December 2018
(This article belongs to the Special Issue Extracellular Vesicles and Metastatic Niche)
Glioblastoma multiforme (GBM) is the most aggressive form of adult primary malignant brain tumour with poor prognosis. Extracellular vesicles (EVs) are a key-mediator through which GBM cells promote a pro-oncogenic microenvironment. Peptidylarginine deiminases (PADs), which catalyze the post-translational protein deimination of target proteins, are implicated in cancer, including via EV modulation. Pan-PAD inhibitor Cl-amidine affected EV release from GBM cells, and EV related microRNA cargo, with reduced pro-oncogenic microRNA21 and increased anti-oncogenic microRNA126, also in combinatory treatment with the chemotherapeutic agent temozolomide (TMZ). The GBM cell lines under study, LN18 and LN229, differed in PAD2, PAD3 and PAD4 isozyme expression. Various cytoskeletal, nuclear and mitochondrial proteins were identified to be deiminated in GBM, including prohibitin (PHB), a key protein in mitochondrial integrity and also involved in chemo-resistance. Post-translational deimination of PHB, and PHB protein levels, were reduced after 1 h treatment with pan-PAD inhibitor Cl-amidine in GBM cells. Histone H3 deimination was also reduced following Cl-amidine treatment. Multifaceted roles for PADs on EV-mediated pathways, as well as deimination of mitochondrial, nuclear and invadopodia related proteins, highlight PADs as novel targets for modulating GBM tumour communication. View Full-Text
Keywords: glioblastoma multiforme (GBM); peptidylarginine deiminase (PAD); extracellular vesicles (EVs); prohibitin (PHB); deiminated histone H3 glioblastoma multiforme (GBM); peptidylarginine deiminase (PAD); extracellular vesicles (EVs); prohibitin (PHB); deiminated histone H3
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MDPI and ACS Style

Kosgodage, U.S.; Uysal-Onganer, P.; MacLatchy, A.; Kraev, I.; Chatterton, N.P.; Nicholas, A.P.; Inal, J.M.; Lange, S. Peptidylarginine Deiminases Post-Translationally Deiminate Prohibitin and Modulate Extracellular Vesicle Release and MicroRNAs in Glioblastoma Multiforme. Int. J. Mol. Sci. 2019, 20, 103. https://doi.org/10.3390/ijms20010103

AMA Style

Kosgodage US, Uysal-Onganer P, MacLatchy A, Kraev I, Chatterton NP, Nicholas AP, Inal JM, Lange S. Peptidylarginine Deiminases Post-Translationally Deiminate Prohibitin and Modulate Extracellular Vesicle Release and MicroRNAs in Glioblastoma Multiforme. International Journal of Molecular Sciences. 2019; 20(1):103. https://doi.org/10.3390/ijms20010103

Chicago/Turabian Style

Kosgodage, Uchini S., Pinar Uysal-Onganer, Amy MacLatchy, Igor Kraev, Nicholas P. Chatterton, Anthony P. Nicholas, Jameel M. Inal, and Sigrun Lange. 2019. "Peptidylarginine Deiminases Post-Translationally Deiminate Prohibitin and Modulate Extracellular Vesicle Release and MicroRNAs in Glioblastoma Multiforme" International Journal of Molecular Sciences 20, no. 1: 103. https://doi.org/10.3390/ijms20010103

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