Pharmacological inhibition of GSK3 promotes TNFα-induced GM-CSF via up-regulation of ERK signaling in nasopharyngeal carcinoma (NPC)

Abstract

Granulocyte-macrophage colony stimulating factor (GM-CSF) functions to drive nasopharyngeal cancer (NPC) metastasis via recruitment and activation of macrophages. However, the source and the regulation of GM-CSF in tumor microenvironment of NPC are not fully understood. In this study, we found that TNFα induced GM-CSF production in NPC CNE1, CNE2, and 5-8F cells in time- and dose-dependent manners. GM-CSF production was tolerant, because the pre-treatment of NPC cells with TNFα down-regulated the GM-CSF production induced by TNFα re-treatment. TNFα activated glycogen synthase kinase-3 (GSK-3), which is an enzyme to regulate glycogen synthesis, and also is a critical downstream element of the PI3K/Akt to regulate cell survival. GSK3 inhibitors up-regulated TNFα-induced GM-CSF, and reversed GM-CSF tolerance induced by TNFα pre-treatment, suggesting that GSK3 activation down-regulated GM-CSF production. GM-CSF down-regulation was not related to ubiquitin-editing enzyme A20. The over-expression of A20 did not regulate GM-CSF production induced by TNFα. However, GSK3 inhibitors up-regulated ERK activation, which contributed to the production of GM-CSF induced by TNFα, suggesting that GSK3 negatively regulated TNFα-induced GM-CSF via down-regulation of ERK signaling. Taking together, these results suggested that GSK3 pathway may be a target for the regulation of TNFα-induced GM-CSF in the tumor microenvironment.