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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Liao Y,Zhao J,Bulek K,Tang F,Chen X,Cai G,Jia S,Fox PL,Huang E,Pizarro TT,Kalady MF,Jackson MW,Bao S,Sen GC,Stark GR,Chang CJ,Li X

doi

10.1038/s41467-020-14698-y

subject

Has Abstract

pub_date

2020-02-14 00:00:00

pages

900

issue

1

issn

2041-1723

pii

10.1038/s41467-020-14698-y

journal_volume

11

pub_type

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