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

Hernandez-Fernaud, J. R. et al. (2017) Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nature Communications, 8, 14206. (doi: 10.1038/ncomms14206) (PMID:28198360) (PMCID:PMC5316871)

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.

• Item Type: Articles
• Additional Information: This work was funded by Cancer Research U.K. (C596/A17196 and C596/A12935 (S.Z.); C596/A18277 (J.C.N.)); Breast Cancer Now Pilot Grants (2012 May SP001, 2014 Nov SP442) (S.Z.); Federal Government Belgium grant (IUAP P7/03), long-term structural Methusalem funding by the Flemish Government, the Research Foundation Flanders (FWO), Foundation against cancer, an European Research Council (ERC) Advanced Research Grant (EUERC269073) and the AXA Research Fund (P.C.)
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Yin, Professor Huabing and Pulleine, Miss Ellie and Zanivan, Professor Sara and Blyth, Professor Karen and Ennis, Dr Darren and Cloix, Dr Catherine and MacPherson, Professor Iain and Norman, Professor James and Neilson, Ms Lisa and Lilla, Dr Sergio and Ismail, Dr Shehab and Mcneish, Professor Iain and McDonald, Dr Laura and Van Den Berghe, Dr Peter
• Authors: Hernandez-Fernaud, J. R., Ruengeler, E., Casazza, A., Neilson, L. J., Pulleine, E., Santi, A., Ismail, S., Lilla, S., Dhayade, S., MacPherson, I. R., McNeish, I., Ennis, D., Ali, H., Kugeratski, F. G., Al Khamici, H., van den Biggelaar, M., van den Berghe, P. V.E., Cloix, C., McDonald, L., Millan, D., Hoyle, A., Kuchnio, A., Carmeliet, P., Valenzuela, S. M., Blyth, K., Yin, H., Mazzone, M., Norman, J. C., and Zanivan, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Science and Engineering > School of Engineering > Biomedical Engineering
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Nature Communications 8: 14206
• Publisher Policy: Reproduced under a Creative Commons License