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

O-GlcNAcylation is a dynamic O-linked glycosylation event that plays a crucial role in regulating cellular signaling. Recent studies indicate that increased O-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 O-GlcNAcylation in the tumor microenvironment (TME) is not fully elucidated. Here, B16 melanoma cells were subcutaneously transplanted into O-GlcNAc transferase transgenic (Ogt-Tg) mice exhibiting elevated O-GlcNAcylation to examine the effect of O-GlcNAcylation in the TME on tumor progression. In this model system, B16 tumor growth was significantly higher in Ogt-Tg/+ mice compared with wild-type (WT) mice. The tumors grown in Ogt-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 Ogt-Tg/+ mice than in those from WT mice. Activation of NF-B, a key regulator in the cytokine production, was downregulated in the macrophages of the tumor tissues grown in Ogt-Tg/+ mice. These data reveal that elevated O-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. Implications: The reduced production of inflammatory cytokine...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signal Transduction Source Type: research