Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages
Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages
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DOI：
10.1016/j.celrep.2017.11.014
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发表时间：
2017-11-28
期刊：
影响因子：
8.8
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
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作者：
Nakatsumi, Hirokazu;Matsumoto, Masaki;Nakayama, Keiichi I.
C-C趋化因子配体2（CCL 2）在肿瘤的形成、发展和转移中起关键作用。尽管已经发现CCL 2的表达依赖于核因子（NF）-κ B信号通路，但肿瘤细胞中CCL 2产生的调节仍然不清楚。我们已经确定了一个非经典的途径来调节CCL 2的生产，这是介导的哺乳动物靶雷帕霉素复合物1（mTORC 1），但独立的NF-κ B。多种磷酸化蛋白质组学方法将转录因子叉头盒K1（FOXK 1）鉴定为mTORC 1的下游靶点。mTORC 1的激活诱导FOXK 1的去磷酸化，导致CCL 2基因的反式激活。mTORC 1-FOXK 1轴的抑制减弱了胰岛素诱导的CCL 2产生以及小鼠中肿瘤相关单核细胞-巨噬细胞的积累和肿瘤进展。我们的研究结果表明，FOXK 1直接连接mTORC 1信号和CCL 2表达的方式独立于NF-κ B和CCL 2产生的这一途径有助于肿瘤的进展。
C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)-kappa B signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a non-canonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-kappa B. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-kB and that CCL2 produced by this pathway contributes to tumor progression.