Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

Nat Commun. 2017 Feb 15;8:14206. doi: 10.1038/ncomms14206.

Abstract

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology
  • Cell Line, Tumor
  • Chloride Channels / metabolism*
  • Disease Progression*
  • Extracellular Matrix / metabolism
  • Female
  • GTP-Binding Proteins / metabolism
  • Glutathione / metabolism*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Mice, Inbred C57BL
  • Mice, Nude
  • Models, Biological
  • Neoplasm Invasiveness
  • Neoplasms / blood supply
  • Neoplasms / pathology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Oxidoreductases / metabolism
  • Protein Binding
  • Proteome / metabolism
  • Proteomics
  • Survival Analysis
  • Transglutaminases / metabolism
  • Treatment Outcome

Substances

  • CLIC3 protein, human
  • Chloride Channels
  • Proteome
  • Oxidoreductases
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins
  • Glutathione