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. 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.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)