Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours
Article first published online: 30 APR 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 6, pages 935–948, June 2013
How to Cite
Park, J., Morley, T. S. and Scherer, P. E. (2013), Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. EMBO Mol Med, 5: 935–948. doi: 10.1002/emmm.201202006
- Issue published online: 4 JUN 2013
- Article first published online: 30 APR 2013
- Manuscript Accepted: 18 MAR 2013
- Manuscript Revised: 17 MAR 2013
- Manuscript Received: 9 SEP 2012
- breast cancer;
- collagen VI;
Endotrophin is a cleavage product of collagenVIα3 (COL6A3). Here, we explore the relationship between thiazolidinediones (TZDs), endotrophin and cisplatin resistance in the context of a mammary tumour model. COL6A3 levels are increased in response to cisplatin exposure in tumours. Endotrophin, in turn, causes cisplatin resistance. The effects of endotrophin can be bypassed, either through use of COL6 null (COL6−/−) mice or by administering TZDs in wild-type mice (leading to a downregulation of endotrophin). Both approaches sensitize tumours to cisplatin through the suppression of endotrophin-induced epithelial–mesenchymal transition. The beneficial effects of TZDs on cisplatin sensitivity are diminished in COL6−/− mice, whereas endotrophin+ tumours are sensitive to the TZD/cisplatin combination. Therefore, the chemosensitization obtained with TZDs is achieved through a downregulation of endotrophin. Treatment with an endotrophin neutralizing antibody in combination with cisplatin completely inhibits tumour growth of tumour allografts. Combined, our data suggest that endotrophin levels are a strong prognostic marker for the effectiveness of the combination therapy of TZDs with cisplatin, and neutralization of endotrophin activity dramatically improves the therapeutic response to combination therapy.