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 and Xiaoxia Li ()
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Yun Liao: Cleveland Clinic
Junjie Zhao: Cleveland Clinic
Katarzyna Bulek: Cleveland Clinic
Fangqiang Tang: Cleveland Clinic
Xing Chen: Cleveland Clinic
Gang Cai: Cleveland Clinic
Shang Jia: University of California
Paul L. Fox: Cleveland Clinic
Emina Huang: Cleveland Clinic
Theresa T. Pizarro: Case Western Reserve University
Matthew F. Kalady: Cleveland Clinic
Mark W. Jackson: Case Western Reserve University
Shideng Bao: Cleveland Clinic
Ganes C. Sen: Cleveland Clinic
George R. Stark: Cleveland Clinic
Christopher J. Chang: University of California
Xiaoxia Li: Cleveland Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14698-y

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