Published in

Nature Research, Nature Communications, 1(8), 2017

DOI: 10.1038/ncomms14206

Links

Tools

Export citation

Search in Google Scholar

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

Journal article published in 2017 by Juan R. Hernandez-Fernaud, Elena Ruengeler, Andrea Casazza, Lisa J. Neilson, Ellie Pulleine, Alice Santi, Shehab Ismail, Sergio Lilla, Sandeep Dhayade, Iain R. MacPherson, Iain McNeish ORCID, Darren Ennis, Hala Ali, Fernanda G. Kugeratski, Heba Al Khamici and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Green circle
Preprint: archiving allowed
Upload
Red circle
Postprint: archiving forbidden
Green circle
Published version: archiving allowed
Upload
Policy details
Data provided by SHERPA/RoMEO

Abstract

AbstractThe 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.