Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours
Open Access
- 30 April 2013
- journal article
- research article
- Published by Springer Nature in EMBO Molecular Medicine
- Vol. 5 (6), 935-948
- https://doi.org/10.1002/emmm.201202006
Abstract
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.Keywords
This publication has 43 references indexed in Scilit:
- Adipocyte-derived endotrophin promotes malignant tumor progressionJCI Insight, 2012
- Three-Dimensional Collagen I Promotes Gemcitabine Resistance in Pancreatic Cancer through MT1-MMP–Mediated Expression of HMGA2Cancer Research, 2011
- Proangiogenic Contribution of Adiponectin toward Mammary Tumor Growth In vivoClinical Cancer Research, 2009
- Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VIMolecular and Cellular Biology, 2009
- Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and CarboplatinClinical Cancer Research, 2008
- Fat and Beyond: The Diverse Biology of PPARγAnnual Review of Biochemistry, 2008
- The resurgence of platinum-based cancer chemotherapyNature Reviews Cancer, 2007
- Synergy between PPARγ Ligands and Platinum-Based Drugs in CancerCancer Cell, 2007
- PPARγ signaling exacerbates mammary gland tumor developmentGenes & Development, 2004
- Terminal Differentiation of Human Breast Cancer through PPARγMolecular Cell, 1998