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

Nat Commun. 2020 Feb 14;11(1):900. doi: 10.1038/s41467-020-14698-y.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism
  • Colon / immunology*
  • Colon / metabolism
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / metabolism
  • Copper / immunology
  • Copper / metabolism*
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / immunology*
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout

Substances

  • Birc4 protein, mouse
  • Inhibitor of Apoptosis Proteins
  • Interleukin-17
  • Membrane Proteins
  • Tiarp protein, mouse
  • Copper