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.
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.
AIMS Assess/evaluate apoptosis in GBM samples maintained on a microfluidics system in response to GSK3368715 and other PRMT inhibitors, currently in clinical trials, with the ultimate goal of synergising with personalised patient care and precision medicine. Investigate the effect of treating GBM biopsies on-chip with PRMT inhibitors at the molecular level, including RNA and protein modifications. METHOD GBM biopsies are received from Hull Royal Infirmary and maintained on-chip for 8-days. They are perfused with media, at a rate of 3 μl/min, mimicking the in vivo environment and allowing real-time analysis of tumour behaviour. PRMT inhibitors, such as GSK3368715, are added to the media, in conjunction with TMZ, to determine their efficacy ex vivo using a range of techniques, such as: immunohistochemistry, cell viability assays, protein analysis and RNA-sequencing. RESULTS We show that PRMT inhibition increases apoptosis five-fold above the control, untreated GBM-on-chip samples. This is compounded by cell viability assays, which have indicated that cell viability in these post-chip tissues is reduced by 30% upon treatment with 1μM GSK3368715. Additionally, western blot analysis has indicated that PRMT inhibition with GSK3368715 appears to switch the methylation status of fused-in-sarcoma (FUS) protein in GBM biopsies. CONCLUSION These results indicate that PRMT inhibition may not only be a viable target for GBM therapy, but could also highlight a mechanism for re-sensitising MGMT-negative GBM to TMZ. This data produces an exciting argument for further research into the use of this novel inhibitor for improving prognosis for patients diagnosed with this devastating disease.
AIMS The first aim was to measure the changes in the levels of 105 cytokines potentially released by GBM tissue maintained on-chip. The second aim was to compare the cytokine profiles from control GBM tissue and tissue treated with anti-GBM drugs {temozolomide (TMZ) at 1 and 10μM both with 1μM arginine methylation inhibitors}. METHOD Intra-operative tissue biopsies were taken from the tumour and transferred immediately from the operating theatre to Hull University laboratories (< 1 hour). Tissue samples were maintained in a viable state in a bespoke chip device for eight days. The biopsy was perfused (3μl/min) with culture medium, with or without drug treatment. Effluents from the biopsies were collected at 24h intervals. Cytokines levels were measured using the Proteome Profiler Human XL Cytokine Array Kit (R&D Systems), each membrane is spotted with 105 different cytokine antibodies in duplicate. RESULTS Six GBM diagnosed patients (five negative for MGMT) were recruited and studied. Eleven cytokines showed consistent, high level, release from GBM tissue either in control or treated samples: Chitinase3-like1, IL8(CXCL8) ,MCP-1(CCL2 ),MIF(Macrophage migration inhibitory factor), MMP-9(Matrix metallopeptidase 9), Osteopontin(OPN), Serpin E1, VEGF(Vascular endothelial growth factor) ,Apolipoprotein A-I, Angiogenin and Emmprin. Multivariate analysis (PERMANOVA) did not show evidence for differential cytokine release profiles with time (P=0.113), treatment (P=0.629), , nor the combined interaction (P=0.936). CONCLUSION GBM biopsies remained viable on the microfluidic platform, shown by sustained cytokine production cytokines. We have also shown that treatment with TMZ plus arginine methylation inhibitors does not significantly affect cytokine release over an eight day period.
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