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dc.contributor.authorKholia, Sharad
dc.contributor.authorJorfi, Samireh
dc.contributor.authorThompson, Paul R.
dc.contributor.authorCausey, Corey P.
dc.contributor.authorNicholas, Anthony P.
dc.contributor.authorInal, Jameel M.
dc.contributor.authorLange, Sigrun
dc.date.accessioned2018-01-30T22:32:15Z
dc.date.available2018-01-30T22:32:15Z
dc.date.issued2015-06-22
dc.identifier.citationKholia , S , Jorfi , S , Thompson , P R , Causey , C P , Nicholas , A P , Inal , J M & Lange , S 2015 , ' A novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapy ' , Journal of Extracellular Vesicles , vol. 4 , no. 1 , 26192 . https://doi.org/10.3402/jev.v4.26192
dc.identifier.issn2001-3078
dc.identifier.otherPURE: 13068938
dc.identifier.otherPURE UUID: ae954993-64c1-4535-abba-dd858aa496ed
dc.identifier.otherScopus: 84940059236
dc.identifier.urihttp://hdl.handle.net/2299/19675
dc.description© 2015 Sharad Kholia et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in ant medium, provided the original work is properly cited.
dc.description.abstractIntroduction: Protein deimination, defined as the post-translational conversion of protein-bound arginine to citrulline, is carried out by a family of 5 calcium-dependent enzymes, the peptidylarginine deiminases (PADs) and has been linked to various cancers. Cellular microvesicle (MV) release, which is involved in cancer progression, and deimination have not been associated before. We hypothesize that elevated PAD expression, observed in cancers, causes increased MV release in cancer cells and contributes to cancer progression. Background: We have previously reported that inhibition of MV release sensitizes cancer cells to chemotherapeutic drugs. PAD2 and PAD4, the isozymes expressed in patients with malignant tumours, can be inhibited with the pan-PAD-inhibitor chloramidine (Cl-am). We sought to investigate whether Cl-am can inhibitMVrelease andwhether this pathway could be utilized to further increase the sensitivity of cancer cells to drug-directed treatment. Methods: Prostate cancer cells (PC3) were induced to release high levels of MVs upon BzATP stimulation of P2X7 receptors. Western blotting with the pan-protein deimination antibody F95 was used to detect a range of deiminated proteins in cells stimulated to microvesiculate. Changes in deiminated proteins during microvesiculation were revealed by immunoprecipitation and immunoblotting, and mass spectrometry identified deiminated target proteins with putative roles in microvesiculation. Conclusion:We report for the first time a novel function of PADs in the biogenesis of MVs in cancer cells. Our results reveal that during the stimulation of prostate cancer cells (PC3) to microvesiculate, PAD2 and PAD4 expression levels and the deimination of cytoskeletal actin are increased. Pharmacological inhibition of PAD enzyme activity using Cl-am significantly reduced MV release and abrogated the deimination of cytoskeletal actin. We demonstrated that combined Cl-am and methotrexate (MTX) treatment of prostate cancer cells increased the cytotoxic effect of MTX synergistically. Refined PAD inhibitors may form part of a novel combination therapy in cancer treatment.en
dc.format.extent16
dc.language.isoeng
dc.relation.ispartofJournal of Extracellular Vesicles
dc.subjectChloramidine
dc.subjectMicrovesicles
dc.subjectMicrovesiculation
dc.subjectPeptidylarginine deiminases
dc.subjectProstate cancer cells (PC3)
dc.subjectHistology
dc.subjectCell Biology
dc.titleA novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapyen
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Biological and Environmental Sciences
dc.contributor.institutionBiosciences Research Group
dc.description.statusPeer reviewed
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=84940059236&partnerID=8YFLogxK
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.3402/jev.v4.26192
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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