Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours

Jiyoung Park,Philipp E Scherer,Thomas S Morley

doi:10.1002/emmm.201202006

Jiyoung Park, Philipp E Scherer + Show 1 more

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https://doi.org/10.1002/emmm.201202006

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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.

Highlights

The platinum-based chemotherapeutic agent cisplatin has been well established in clinical treatment regimens due to its effectiveness on human tumour cells, such as in the context of ovarian, lung, testicular and breast cancer (Kelland, 2007; Lee et al, 2004; Sirohi et al, 2008)
Cisplatin augments COL6A3 levels, whereas TZDs cause a reduction To assess the beneficial effects of TZD on platinum-based chemotherapies in mammary tumour models in vivo, we used either a MMTVPyMT (‘‘PyMT’’) mouse model or an allograft of Met-1 cancer cells that we transplanted into isogenic wild-type mice
This may be due to peroxisome proliferator-activated receptor gamma (PPARg)-dependent activation of intrinsic oncogenic pathways, such as wnt, or contributions of the tumour stroma responding to a prolonged treatment of TZDs, which may counteract their beneficial effects on cisplatin in the PyMT mice (Saez et al, 2004)

Summary

Introduction

The platinum-based chemotherapeutic agent cisplatin (cisdiammine-dichloro-platinum) has been well established in clinical treatment regimens due to its effectiveness on human tumour cells, such as in the context of ovarian, lung, testicular and breast cancer (Kelland, 2007; Lee et al, 2004; Sirohi et al, 2008). To overcome the drug resistance against platinum-based chemotherapy, combination therapies with peroxisome proliferator-activated receptor gamma (PPARg) agonists, the thiazolidinediones (TZDs), have been performed. The basis for this approach is the growth inhibitory effect of these PPARg agonists on transformed cells through both PPARgdependent and -independent pathways (Blanquicett et al, 2008; Mueller et al, 1998; Palakurthi et al, 2001; Satoh et al, 2002). PPARg is a member of the nuclear hormone receptor superfamily and a key transcription factor for adipogenesis It is involved in various physiological processes, such as cell proliferation, angiogenesis, inflammation and lipid partitioning (Tontonoz & Spiegelman, 2008).

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