Elevated O-GlcNAcylation in the tumor microenvironment promotes B16 melanoma cell progression through the suppression of p38 MAPK

[Speaker] Kazumasa Moriwaki:1
[Co-author] Michio Asahi:1
1:Pharmacology, Faculty of Medicine, Osaka Medical Collage, Japan

O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for a wide range of intracellular signaling. The modification is regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add and remove the modification, respectively. Elevated O-GlcNAcylation is a general feature of cancer cell and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor microenvironment (TME) is not fully elucidated. Here, to examine the role in TME, B16 melanoma cells were subcutaneously transplanted into Ogt transgenic (Ogt-Tg) mice exhibiting systemically elevated O-GlcNAcylation. In this model, B16 tumor growth was significantly higher in Ogt-Tg mice than in wild type (WT) mice. In the tumors excised from Ogt-Tg mice, p38 activity was significantly reduced, while ERK signaling was increased. Moreover, NF-κB activity and inflammatory cytokine production were significantly lower in the tumor and peritoneal macrophages from Ogt-Tg mice than in WT mice. In B16 cells, p38 inhibition accelerated the proliferation through ERK activation. These data suggest that O-GlcNAcylation in the TME may reduce the production of inflammatory cytokines and promote tumor growth through suppression of p38 MAPK followed by upregulation of the ERK pathway. Elevated O-GlcNAcylation in the TME may be one of the mechanisms that diabetes promotes tumor progression.
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