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.
Highlights
Copper levels are known to be elevated in inflamed and malignant tissues
STEAP4 is unique among its family members in that its expression is regulated by proinflammatory cytokines[31]
To determine whether STEAP4 was transcriptionally induced by NFκB or STAT3, we analyzed the induction of STEAP4 expression by IL-17 (NFκB activator) and IL-22 (STAT3 activator)
Summary
Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. 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 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. This study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis. This uptake mechanism entails that Ctr[1] works in conjunction with a metallo-reductase when copper is available as Cu II This two-step paradigm of copper uptake shows that cancer cells need to manipulate the expression of both transporter and reductase in order to regulate intracellular copper levels[16]. We report that STEAP4 is a key metallo-reductase that promotes cellular copper uptake in response to chronic inflammation during colon tumorigenesis. Our study has identified STEAP4 as a regulatory node for inflammation-mediated cellular copper uptake and revealed a mechanism through which inflammation and copper promote tumor progression
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