Augmented TME -GlcNAcylation Promotes Tumor Proliferation through the Inhibition of p38 MAPK.

-GlcNAcylation is a dynamic -linked glycosylation event that plays a crucial role in regulating cellular signaling. Recent studies indicate that increased -GlcNAcylation is a general feature in cancer and contributes to various cancer phenotypes, including cell proliferation, survival, invasion, metastasis, and energy metabolism. However, the role of -GlcNAcylation in the tumor microenvironment (TME) is not fully elucidated. Here, B16 melanoma cells were subcutaneously transplanted into -GlcNAc transferase transgenic (-Tg) mice exhibiting elevated -GlcNAcylation to examine the effect of -GlcNAcylation in the TME on tumor progression. In this model system, B16 tumor growth was significantly higher in -Tg/+ mice compared with wild-type (WT) mice. The tumors grown in -Tg/+ mice showed significant downregulation of p38 MAPK activity and upregulation of the ERK1/2 signaling pathway. In addition, proinflammatory cytokine production was significantly lower in the tumor tissues from -Tg/+ mice than in those from WT mice. Activation of NF-κB, a key regulator in the cytokine production, was downregulated in the macrophages of the tumor tissues grown in -Tg/+ mice. These data reveal that elevated -GlcNAcylation in the TME reduces the production of inflammatory cytokines and promotes cancer progression through downregulation of p38 MAPK activity and subsequent upregulation of the ERK1/2 signaling pathway. The reduced production of inflammatory cytokines by augmented -GlcNAcylation in the TME, mainly macrophages, promotes tumor proliferation through the inhibition of p38 MAPK and suggests a possible cause of increased morbidity and mortality rates for various cancers in diabetic patients. .