Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis

Yun Liao; Junjie Zhao; Katarzyna Bulek; Fangqiang Tang; Xing Chen; Gang Cai; Shang Jia; Paul L. Fox; Emina Huang; Theresa T. Pizarro; Matthew F. Kalady; Mark W. Jackson; Shideng Bao; Ganes C. Sen; George R. Stark; Christopher J. Chang; Xiaoxia Li

doi:10.1038/s41467-020-14698-y

Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis

Yun Liao, Junjie Zhao, Katarzyna Bulek, Fangqiang Tang, Xing Chen, Gang Cai, Shang Jia, Paul L. Fox, Emina Huang, Theresa T. Pizarro, Matthew F. Kalady, Mark W. Jackson, Shideng Bao, Ganes C. Sen, George R. Stark, Christopher J. Chang, Xiaoxia Li

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Abstract

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.

Original language	English (US)
Article number	900
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14698-y
State	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-020-14698-y

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Liao, Y., Zhao, J., Bulek, K., Tang, F., Chen, X., Cai, G., Jia, S., Fox, P. L., Huang, E., Pizarro, T. T., Kalady, M. F., Jackson, M. W., Bao, S., Sen, G. C., Stark, G. R., Chang, C. J., & Li, X. (2020). Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis. Nature communications, 11(1), [900]. https://doi.org/10.1038/s41467-020-14698-y

@article{e88d05820d634aca854e00d7052f36f6,

title = "Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis",

abstract = "Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.",

author = "Yun Liao and Junjie Zhao and Katarzyna Bulek and Fangqiang Tang and Xing Chen and Gang Cai and Shang Jia and Fox, {Paul L.} and Emina Huang and Pizarro, {Theresa T.} and Kalady, {Matthew F.} and Jackson, {Mark W.} and Shideng Bao and Sen, {Ganes C.} and Stark, {George R.} and Chang, {Christopher J.} and Xiaoxia Li",

note = "Funding Information: We thank Dr. Valeria C. Culotta and Dr. Edward M. Culbertson from Johns Hopkins University for help with in-gel SOD1 activity assay. We thank Dr. Wen Qian, Mr. Jianxin Xiao and Mrs. Jing Ma from Cleveland Clinic for technical support. This work was supported by the National Institutes of Health grants (P01CA062220 and P01 HL103453 to X.L., R01CA193359 to M.F.K., GM 79465 to C.J.C. U01 CA 214300 and R01 237304 to E.H. and S10-OD019972 to the Imaging Core at the Lerner Institute at Cleveland Clinic). C.J.C. is an Investigator with the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14698-y",

language = "English (US)",

volume = "11",

journal = "Nature Communications",

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TY - JOUR

T1 - Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis

AU - Liao, Yun

AU - Zhao, Junjie

AU - Bulek, Katarzyna

AU - Tang, Fangqiang

AU - Chen, Xing

AU - Cai, Gang

AU - Jia, Shang

AU - Fox, Paul L.

AU - Huang, Emina

AU - Pizarro, Theresa T.

AU - Kalady, Matthew F.

AU - Jackson, Mark W.

AU - Bao, Shideng

AU - Sen, Ganes C.

AU - Stark, George R.

AU - Chang, Christopher J.

AU - Li, Xiaoxia

N1 - Funding Information: We thank Dr. Valeria C. Culotta and Dr. Edward M. Culbertson from Johns Hopkins University for help with in-gel SOD1 activity assay. We thank Dr. Wen Qian, Mr. Jianxin Xiao and Mrs. Jing Ma from Cleveland Clinic for technical support. This work was supported by the National Institutes of Health grants (P01CA062220 and P01 HL103453 to X.L., R01CA193359 to M.F.K., GM 79465 to C.J.C. U01 CA 214300 and R01 237304 to E.H. and S10-OD019972 to the Imaging Core at the Lerner Institute at Cleveland Clinic). C.J.C. is an Investigator with the Howard Hughes Medical Institute. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.

AB - Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.

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JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 900

ER -

Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis

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