关键词: 胶质瘤相关巨噬细胞, 糖酵解, 乳酸脱氢酶抑制剂

Abstract: Objective To explore the effects and mechanisms involved in glioma conditioned medium for inducing glycolysis and oncogenic mediators in macrophages. Methods Bone marrow derived macrophage (BMDM) induced by hypoxia and mouse glioma cell line GL261 conditioned medium (GCM)(GCM-BMDM) were used as a model. The mRNA level of M1 and M2 oncogenic mediators, hypoxia-inducible factor-1α (HIF-1α) and glycolysis associated genes in GCM-BMDM were detected by qPCR. The extracellular acidification rate (ECAR) of GCM-BMDM was detected by Seahorse bioenergy assay method. The protein levels of signal transducer and activator of transcription 6 (STAT6), signal transducer and activator of transcription 3(STAT3) and their phosphorylated forms p-STAT6 and p-STAT3 were examined by Western blot. Results GCM stimulated mRNA expression of Hif-1α and a variety of M1 and M2 oncogenic mediators in BMDM (P＜0.01). GCM upregulated the mRNA expression of multiple glycolysis associated genes (P＜0.01) and increased glycolysis level in BMDM (P＜0.001). The glycolysis level was reduced by incubation with lactate dehydrogenase inhibitor stiripentol (STP) (P＜0.05). STP down-regulated mRNA levels of Hif-1α and oncogenic mediators Il-1β, Il-6, Ido and Cd163 in GCM-BMDM(P＜0.01). STP decreased the ratio of p-STAT3 /STAT3 and p-STAT6 /STAT6 in GCM-BMDM (P＜0.05). Conclusions GCM increases glycolysis level and induces the pro-tumoral phenotypes in GAMs through promoting transcriptional regulation mediated by HIF-1α, STAT3 and STAT6. STP can effectively reduce glycolysis and transcriptional expression of oncogenic mediators in GAMs.

Key words: glioma associated macrophage, glycolysis, lactate dehydrogenase inhibitor