Iron accelerates Fusobacterium nucleatum–induced CCL8 expression in macrophages and is associated with colorectal cancer progression
Taishi Yamane, … , Hideo Baba, Toshiro Moroishi
Taishi Yamane, … , Hideo Baba, Toshiro Moroishi
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(21):e156802. https://doi.org/10.1172/jci.insight.156802.
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Research Article Oncology

Iron accelerates Fusobacterium nucleatum–induced CCL8 expression in macrophages and is associated with colorectal cancer progression

Abstract

Accumulating evidence suggests that high levels of Fusobacterium nucleatum in colorectal tumor tissues can be associated with poor prognosis in patients with colorectal cancer (CRC); however, data regarding distinct prognostic subgroups in F. nucleatum–positive CRC remain limited. Herein, we demonstrate that high-iron status was associated with a worse prognosis in patients with CRC with F. nucleatum. Patients with CRC presenting elevated serum transferrin saturation exhibited preferential iron deposition in macrophages in the tumor microenvironment. In addition, F. nucleatum induced CCL8 expression in macrophages via the TLR4/NF-κB signaling pathway, which was inhibited by iron deficiency. Mechanistically, iron attenuated the inhibitory phosphorylation of NF-κB p65 by activating serine/threonine phosphatases, augmenting tumor-promoting chemokine production in macrophages. Our observations indicate a key role for iron in modulating the NF-κB signaling pathway and suggest its prognostic potential as a determining factor for interpatient heterogeneity in F. nucleatum–positive CRC.

Authors

Taishi Yamane, Yohei Kanamori, Hiroshi Sawayama, Hiromu Yano, Akihiro Nita, Yudai Ohta, Hironori Hinokuma, Ayato Maeda, Akiko Iwai, Takashi Matsumoto, Mayuko Shimoda, Mayumi Niimura, Shingo Usuki, Noriko Yasuda-Yoshihara, Masato Niwa, Yoshifumi Baba, Takatsugu Ishimoto, Yoshihiro Komohara, Tomohiro Sawa, Tasuku Hirayama, Hideo Baba, Toshiro Moroishi

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Figure 5

Protein phosphatases PP1 and PP2A require iron to limit inhibitory phosphorylation of NF-κB p65 upon TLR4 activation.

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Protein phosphatases PP1 and PP2A require iron to limit inhibitory phosp...
(A) IKKα/β expression was undetectable in IKK-KO THP-1 cells. Immunoblot analysis of IKKα and IKKβ in WT, IKK-KO, IKKβ-KO and IKKα/β double-KO (dKO) THP-1 cells is shown. (B) Deletion of IKKα did not suppress iron chelation–induced inhibitory phosphorylation of NF-κB p65 at S536. WT and IKKα-KO THP-1 cells were pretreated with deferoxamine (DFO; 100 μM) for 8 hours, followed by treatment with LPS (100 ng/mL) for 1 hour. Immunoblot analysis of NF-κB p65 phosphorylation at S536 is shown. (C) Deletion of IKKβ has no effect on iron chelation–induced inhibitory phosphorylation of NF-κB p65 at S536. WT and IKK-KO THP-1 cells were treated with DFO (100 μM) for 8 hours prior to LPS (100 ng/mL) treatment for 1 hour and then subjected to immunoblot analysis. (D) Dual inhibition of IKKα and IKKβ blocks S536 phosphorylation of NF-κB p65. WT and IKKα/β dKO THP-1 cells were treated with DFO (100 μM) for 8 hours prior to LPS (100 ng/mL) treatment for 1 hour, followed by immunoblot analysis. (E) Iron deficiency enhances the inhibitory phosphorylation of NF-κB p65 by inhibiting the protein phosphatase PP1/PP2A. THP-1 cells were treated with DFO (100 μM) for 8 hours and stimulated with LPS (100 ng/mL) for 1 hour in the presence or absence of calyculin A. Immunoblot analysis of NF-κB p65 phosphorylation at S536 is shown.