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

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.

SUBMITTER: Hernandez-Fernaud JR

PROVIDER: S-EPMC5316871 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Hernandez-Fernaud Juan R JR Ruengeler Elena E Casazza Andrea A Neilson Lisa J LJ Pulleine Ellie E Santi Alice A Ismail Shehab S Lilla Sergio S Dhayade Sandeep S MacPherson Iain R IR McNeish Iain I Ennis Darren D Ali Hala H Kugeratski Fernanda G FG Al Khamici Heba H van den Biggelaar Maartje M van den Berghe Peter V E PV Cloix Catherine C McDonald Laura L Millan David D Hoyle Aoisha A Kuchnio Anna A Carmeliet Peter P Valenzuela Stella M SM Blyth Karen K Yin Huabing H Mazzone Massimiliano M Norman Jim C JC Zanivan Sara S

Nature communications 20170215

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 ...[more]

PMID: 28198360

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

Publications

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

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