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)

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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:Neilson, Ms Lisa and Yin, Professor Huabing and Lilla, Dr Sergio and Pulleine, Miss Ellie and Zanivan, Dr Sara Rossana and Mcneish, Professor Iain and McDonald, Dr Laura and Blyth, Dr Karen and Ennis, Dr Darren and Cloix, Dr Catherine and MacPherson, Dr Iain and Van Den Berghe, Dr Peter and Norman, Professor James
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 > Institute of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Nature Communications
Publisher:Nature Publishing Group
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

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