Department of Clinical Laboratory, Changsha Central Hospital, University of South China, Changsha 410004, China; Medical Research Center, Changsha Central Hospital, University of South China, Changsha 410004, China.
Department of Clinical Laboratory, Changsha Central Hospital, University of South China, Changsha 410004, China.
Int Immunopharmacol. 2020 Jun;83:106447. doi: 10.1016/j.intimp.2020.106447. Epub 2020 Apr 2.
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.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）通过招募和激活巨噬细胞来促进鼻咽癌（NPC）的转移。然而，NPC 肿瘤微环境中 GM-CSF 的来源和调控机制尚不完全清楚。在本研究中，我们发现 TNFα 以时间和剂量依赖的方式诱导 NPC CNE1、CNE2 和 5-8F 细胞产生 GM-CSF。GM-CSF 的产生具有耐受性，因为 NPC 细胞先用 TNFα 预处理会下调 TNFα 再处理诱导的 GM-CSF 产生。TNFα 激活了糖原合成激酶-3（GSK-3），GSK-3 是一种调节糖原合成的酶，也是调节细胞存活的 PI3K/Akt 的关键下游元件。GSK3 抑制剂上调 TNFα 诱导的 GM-CSF，并逆转 TNFα 预处理诱导的 GM-CSF 耐受性，表明 GSK3 激活下调了 GM-CSF 的产生。GM-CSF 的下调与泛素编辑酶 A20 无关。A20 的过表达并不调节 TNFα 诱导的 GM-CSF 产生。然而，GSK3 抑制剂上调了 ERK 的激活，这有助于 TNFα 诱导的 GM-CSF 的产生，表明 GSK3 通过下调 ERK 信号通路负调控 TNFα 诱导的 GM-CSF。综上所述，这些结果表明 GSK3 通路可能是调节 TNFα 在肿瘤微环境中诱导 GM-CSF 的靶点。
