期刊
CELL REPORTS
卷 21, 期 9, 页码 2471-2486出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.11.014
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资金
- Japan Society for the Promotion of Science KAKENHI [24770129, 26830078, 25221303]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [17K19606, 24770129, 26830078, 17H06011, 16H04730, 17H05534] Funding Source: KAKEN
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.
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