Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages

• Published in: Cell reports (Cambridge) Vol. 21; no. 9; pp. 2471 - 2486
• Main Authors: Nakatsumi, Hirokazu, Matsumoto, Masaki, Nakayama, Keiichi I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.11.2017; Elsevier
• Subjects: cancer; cancer-related inflammation; CCL2; chronic inflammation; FOXK1; mTORC1; nutrition; phosphoproteomics; tumor; tumor-associated macrophage; phosphoproteomics; nutrition; tumor; tumor-associated macrophage; cancer-related inflammation; CCL2; FOXK1; cancer; mTORC1; chronic inflammation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.11.014

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)-κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. 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-κB and that CCL2 produced by this pathway contributes to tumor progression. [Display omitted] •mTORC1 regulates CCL2 expression via FOXK1 activation•FOXK1 is dephosphorylated and thereby activated in response to mTORC1 activation•The mTORC1-FOXK1-CCL2 pathway is independent of classical NF-κB signaling•This pathway promotes macrophage accumulation and associated tumor growth Nakatsumi et al. show that mTORC1 regulates CCL2 expression in a manner independent of NF-κB signaling by dephosphorylating the transcription factor FOXK1. Moreover, they demonstrate that hyperactivation of mTORC1 results in attraction of M2-type tumor-associated macrophages and promotes tumor growth in vivo via the mTORC1-FOXK1-CCL2 pathway.