Inhibiting Arginine Methylation as a Tool to Investigate Cross-Talk with Methylation and Acetylation Post-Translational Modifications in a Glioblastoma Cell Line

Samuel, Sabrina Francesca; Marsden, Alistair James; Deepak, Srihari; Rivero, Francisco; Greenman, John; Beltrán-Álvarez, Pedro

doi:10.3390/proteomes6040044

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…Furamidine has been used as a specific PRMT1 inhibitor at low µM concentrations. 23,[45][46][47][48] Furamidine is also known to have other effects including as an anti-protozoal agent, 49 DNA binding and inhibitor of tyrosyl-DNA phosphodiesterase 1. 50 These alternative activities of furamidine are unlikely to be relevant in the context of washed or circulating platelets and furamidine treatment reduced the intensity of ArgMe bands, which supports the idea that the reported inhibition of platelet function is due to direct inhibition of PRMT activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Arginine Methylation Impairs Platelet Function

Marsden

Riley

Barry

et al. 2021

ACS Pharmacol. Transl. Sci.

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Protein arginine methyltransferases (PRMTs) catalyse the transfer of methyl groups to arginine residues in proteins. PRMT inhibitors are novel, promising drugs against cancer that are currently in clinical trials, which include oral administration of the drugs. However, off-target activities of systemically available PRMT inhibitorshave not yet been investigated. In this work, we study the relevance of arginine methylation in platelets and investigate the effect of PRMT inhibitors on platelet function and on the expression of relevant platelet receptors.We show that (1) key platelet proteins are modified by arginine methylation, (2) incubation of human platelets with PRMT inhibitors for 4 hours results in impaired capacity of platelets to aggregate in response to thrombin and collagen, with IC50 values in the µM range, and (3) treatment with PRMT inhibitors leads to decreased membrane expression and reduced activation of the critical platelet integrin αIIbβ3. Our contribution opens new avenues for research on arginine methylation in platelets, including the repurposing of arginine methylation inhibitors as novel antiplatelet drugs. We also recommend that current and future clinical trials with PRMT inhibitors consider any adverse effects associated with platelet inhibition of these emerging anti-cancer drugs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Arginine Methylation Impairs Platelet Function

Marsden

Riley

Barry

et al. 2021

ACS Pharmacol. Transl. Sci.

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“…Induction of apoptosis was also observed by TUNEL assay (Wang et al 2012c ). More recently, inhibition of PRMT1 by furamidine has been suggested to reduce GBM cell viability (Samuel et al 2018 ).…”

Section: Arginine Methylation In Gbmmentioning

confidence: 99%

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

et al. 2021

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Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT–protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.

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“…Among subcategories of brain tumors, GBM is the most well studied regarding its association with arginine methylation [ 12 , 13 , 16 , 75 , 113 , 114 , 115 ]. This related to the importance of GBM as the most common and deadly malignant brain neoplasm [ 116 ].…”

Section: Role Of Prmts In Tumorigenesismentioning

confidence: 99%

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

Bryant

Heiss

Banasavadi-Siddegowda

2021

Cells

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Protein arginine methylation is a common post-translational modification that plays a pivotal role in cellular regulation. Protein arginine methyltransferases (PRMTs) catalyze the modification of target proteins by adding methyl groups to the guanidino nitrogen atoms of arginine residues. Protein arginine methylation takes part in epigenetic and cellular regulation and has been linked to neurodegenerative diseases, metabolic diseases, and tumor progression. Aberrant expression of PRMTs is associated with the development of brain tumors such as glioblastoma and medulloblastoma. Identifying PRMTs as plausible contributors to tumorigenesis has led to preclinical and clinical investigations of PRMT inhibitors for glioblastoma and medulloblastoma therapy. In this review, we discuss the role of arginine methylation in cancer biology and provide an update on the use of small molecule inhibitors of PRMTs to treat glioblastoma, medulloblastoma, and other cancers.

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Inhibiting Arginine Methylation as a Tool to Investigate Cross-Talk with Methylation and Acetylation Post-Translational Modifications in a Glioblastoma Cell Line

Cited by 8 publications

References 48 publications

Inhibition of Arginine Methylation Impairs Platelet Function

Inhibition of Arginine Methylation Impairs Platelet Function

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

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