LLY-283

Protein methylation is a prevalent post-translational modification after cerebral ischemia. Protein arginine methyltransferase 5 (PRMT5) is a type of methyltransferase enzyme that can catalyse the formation of methylated residues on histones and non-histone proteins. Accumulating evidence suggested that PRMT5 might play a carcinogenic role in various cancers. However, the role of PRMT5 in cerebral ischaemia/reperfusion (I/R) injury remains unclear. In this project, middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model in human neuroblastoma SH-SY5Y cells were utilized to mimic disease state of cerebral I/R. We found that expression of inflammatory-related factors [Interleukin (IL)-1β and IL-6)] and pyroptotic-related factor [N-term cleaved Gasdermin-D (GSDMD-N)] were up-regulated in both MCAO/R mice and OGD/R SH-SY5Y cells. In addition, both in vivo and in vitro, PRMT5 was aberrantly upregulated during cerebral I/R. However, these alterations induced by I/R were blocked by PRMT5 inhibitor LLY-283, and enhanced by overexpression of PRMT5. Furthermore, rescue experiment proved that PRMT5 plays a pro-inflammatory and pro-pyroptotic role by activating nuclear factor kappa B (NF-κB)/nucleotide-binding oligomerization domainlike receptor pyrin domain containing 3 (NLRP3) axis. Finally, we observed that treatment of LLY-283 alleviated neurological deficits and reduced infarct volume in the MCAO/R mice. Taken together, PRMT5 may be a potential therapeutic target for cerebral I/R injury.

To explore the effect of LLY-283 on the biological behavior of Head and neck squamous cell carcinoma(HNSCC) proliferation and metastasis through protein arginine methyltransferase 5(PRMT5).

TCGA database was used to analyze the expression level of PRMT5 in HNSCC tissues and cell lines by RT-PCR and Western blot. Lentiviral technology was used to construct PRMT5 knockdown stable cell line, and analyze the effect of PRMT5 on the biological behavior of HNSCC. Drug killing experiment was used to observe the IC50 changes of LLY-283 in cell lines. Nude mouse xenograft experiments were further tested to observe the biological effects of LLY-283 on HNSCC through PRMT5.

PRMT5 was highly expressed in HNSCC tissues and cell lines, which promoted the proliferation and metastasis of cell lines, and reduced the IC50 value of LLY-283. LLY-283 could significantly reduce the cell proliferation and metastasis, tumor volume and Ki-67 expression in nude mice in vivo of HNSCC through PRMT5.

LLY-283 inhibits the expression of PRMT5 and Ki-67, thereby decreases the proliferation and metastasis of HNSCC and the ability to form transplanted tumors in nude mice, exerting anti-tumor effects.