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

Nakatsumi, Hirokazu; Matsumoto, Masaki; Nakayama, Keiichi I.

doi:10.1016/j.celrep.2017.11.014

Cited by 93 publications

(91 citation statements)

References 45 publications

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“…Instances of variable dysregulation could be due to compensatory mechanisms or interdependence of specific mediators, as in the case of TNF and Egr1 37 . The data also demonstrate that not all signaling is impaired by TAK1‐inhibition (e.g., CCL2), suggesting predominant/compensatory control by signaling cascades with TAK1‐independent aspects such as the mTOR/FOXK1 axis 65 . TAK1 has long been known to be an important player in various signaling‐induced outcomes, including inflammation driven by other cell types, and in other disease models.…”

Section: Discussionmentioning

confidence: 77%

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Watson

Maguire

Rouillard

et al. 2020

Journal of Leukocyte Biology

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Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro‐inflammatory mediators in response to environmental cues detected by the IgE‐FcεRI complex. The role of TGF‐β‐activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE‐mediated activation under SCF‐c‐kit potentiation in a mast cell‐driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z‐7‐oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell‐mediated responses using IgE‐sensitized murine bone marrow‐derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF‐κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro‐inflammatory cytokines TNF, IL‐6, IL‐13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1‐inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF‐κB pathways in driving the late‐phase response, but also initiation of the degranulation mechanism of the mast cell early‐phase response following allergen recognition and may warrant consideration in future therapeutic development.

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Section: Discussionmentioning

confidence: 77%

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Watson

Maguire

Rouillard

et al. 2020

Journal of Leukocyte Biology

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“…The mTORC1-FOXK1 pathway senses amino acid changes in CM and regulates CCL2 expression independent of NF-κB signaling by dephosphorylating the transcription factor FOXK1. 45 We tested the activation of the mTORC1-FOXK1 pathway in MΦ, MS, and MR and found that activation of the mTORC1-FOXK1 pathway was consistent with the secretion trend of CCL2 ( Figure 3C). These results suggest that TNFα and amino acid metabolism in CM activate the NF-κB and mTORC1-FOXK1 pathways of TAM promoting the secretion of CCL2.…”

Section: Tumor Necrosis Factor Alpha and Amino Acid Metabolism In Cmentioning

confidence: 74%

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

et al. 2019

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Abbreviations: CCL2, CC-chemokine ligand 2; CM, conditioned medium; ER, estrogen receptor; MCP-1, monocyte chemoattractant protein 1; MR, tumor-associated macrophage from a tamoxifen-resistant tumor microenvironment; MS, tumor-associated macrophage from a tamoxifen-sensitive tumor microenvironment; PFS, progression-free survival; TAM, tumor-associated macrophage; TME, tumor microenvironment. AbstractBreast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrineresistant breast cancer.

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“…Although mTORC1 induces dephosphorylation of FOXK1 via PP2A, the signaling cascade has not been fully uncovered (Nakatsumi et al, 2017). In the present study, we identified B56 as the B subunit of PP2A that is required for the FOXK1 dephosphorylation.…”

Section: Discussionmentioning

confidence: 65%

“…We previously showed that mTORC1 induces PP2Amediated multiple dephosphorylation of the transcription factor forkhead box K1 (FOXK1) (Nakatsumi, Matsumoto, & Nakayama, 2017). The dephosphorylated FOXK1 transactivates C-C chemokine ligand 2 (CCL2), a proinflammatory chemokine that promotes the accumulation of monocytesmacrophages at inflammatory sites (Deshmane, Kremlev, Amini, & Sawaya, 2009;Matsushima, Larsen, DuBois, & Oppenheim, 1989).…”

Section: Introductionmentioning

confidence: 99%

“…The dephosphorylated FOXK1 transactivates C-C chemokine ligand 2 (CCL2), a proinflammatory chemokine that promotes the accumulation of monocytesmacrophages at inflammatory sites (Deshmane, Kremlev, Amini, & Sawaya, 2009;Matsushima, Larsen, DuBois, & Oppenheim, 1989). Consistent with the fact that hyperactivation of mTORC1 is frequently observed in various types of cancer (Menon & Manning, 2008), mTORC1 activates FOXK1-dependent transcription of CCL2 to recruit tumor-associated macrophages (TAMs) to the tumor tissues (Nakatsumi et al, 2017). The mechanistic link between mTORC1 activation and FOXK1 dephosphorylation has been poorly understood, however.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear–cytoplasmic shuttling protein PP2A^B56 contributes to mTORC1‐dependent dephosphorylation of FOXK1

et al. 2018

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Mammalian target of rapamycin complex 1 (mTORC1) kinase is a master regulator of the cellular response to nutrition-related signals such as insulin and amino acids. mTORC1 is activated on the lysosomal membrane and induces phosphorylation of a variety of downstream molecules. We previously showed that activated mTORC1 induces protein phosphatase 2A (PP2A)-mediated dephosphorylation of the transcription factor forkhead box K1 (FOXK1). The mechanism underlying the signal transduction from the cytoplasmic mTORC1 to the nuclear FOXK1 has remained unclear, however, we now show that a nuclear-cytoplasmic transport system is necessary for the mTORC1-FOXK1 signal transduction. This reaction is mediated by a shuttling protein B56, which is a regulatory subunit of PP2A and plays an essential role in the mTORC1-dependent dephosphorylation of FOXK1. These results suggest that PP2A phosphatase contributes to the signaling for mTORC1-dependent transcriptional regulation.

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

Cited by 93 publications

References 45 publications

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

Nuclear–cytoplasmic shuttling protein PP2A^B56 contributes to mTORC1‐dependent dephosphorylation of FOXK1

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

Cited by 93 publications

References 45 publications

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

Nuclear–cytoplasmic shuttling protein PP2AB56 contributes to mTORC1‐dependent dephosphorylation of FOXK1

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Nuclear–cytoplasmic shuttling protein PP2A^B56 contributes to mTORC1‐dependent dephosphorylation of FOXK1