Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma.

Recently, crystallographic studies have demonstrated that BMS-202, a small-molecule compound characterized by a methoxy-1-pyridine chemical structure, exhibits a high affinity to PD-L1 dimerization. However, its roles and mechanisms in glioblastoma (GBM) remain unclear. The objective of this study is to investigate the antitumor activity of BMS-202 and its underlying mechanisms in GBM using multi-omics and bioinformatics techniques, along with a majority of in vitro and in vivo experiments, including CCK-8 assays, flow cytometry, co-immunoprecipitation, siRNA transfection, PCR, western blotting, cell migration/invasion assays and xenografts therapeutic assays. Our findings indicate that BMS-202 apparently inhibits the proliferation of GBM cells both in vitro and in vivo. Besides, it functionally blocks cell migration and invasion in vitro. Mechanistically, it reduces the expression of PD-L1 on the surface of GBM cells and interrupts the PD-L1-AKT-BCAT1 axis independent of mTOR signaling. Taken together, we conclude that BMS-202 is a promising therapeutic candidate for patients with GBM by remodeling their cell metabolism regimen, thus leading to better survival.

P4HA1 as an unfavorable prognostic marker promotes cell migration and invasion of glioblastoma via inducing EMT process under hypoxia microenvironment.

This study aims to explore the mechanism of glioblastoma multiforme (GBM) in hypoxia through metabolomic and proteomic analysis. We showed that the migration and invasiveness of LN18 cells was significantly enhanced after 24 h of hypoxia treatment. The metabolomic and proteomic profiling were conducted in LN18 cells cultured under hypoxia condition. Correlation analysis between significant differential metabolites and proteins revealed seven proteins and ten metabolites, of which metabolite L-Arg was negatively correlated with P4HA1 protein. Meanwhile, the expression of HIF1α, nNOS and P4HA1 was up-regulated, and the concentration of L-Arg and NO was decreased and increased respectively. Knockdown of HIF1α reduced the expression of nNOS and P4HA1, the concentration of NO and the invasiveness of cells, while increased the concentration of L-Arg. Similar changes on P4HA1 expression, the concentration of L-Arg and NO were observed when the expression of nNOS was disrupted. Lastly, knockdown of P4HA1 impaired the invasion of LN18 and T98G cells, probably through regulating the expression of Vimentin, MMP2, MMP9, Snail and E-cadherin. Consistent trends on both the overexpression of these relevant genes, as well as the concentration of L-Arg and NO were also observed in all our overexpression experiments. Besides, we investigated the relationship between P4HA1 expression and prognosis by MTA, CGGA and TCGA databases. Increased P4HA1 level was correlated poor prognosis with advanced histological grade. In summary, we found that hypoxia promotes the migration and invasion of GBM via the L-Arg/P4HA1 axis which maybe an effective molecular marker or predictor of clinical outcome in GBM patients.