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

Jiyoung Park, Thomas S. Morley, Philipp E. Scherer

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)935-948
Number of pages14
JournalEMBO Molecular Medicine
Volume5
Issue number6
DOIs
StatePublished - Jun 2013

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Cisplatin
Collagen
Thiazolidinediones
Neoplasms
endotrophin
Down-Regulation
Epithelial-Mesenchymal Transition
Neutralizing Antibodies
Allografts
Therapeutics
Breast Neoplasms
Growth

Keywords

  • Breast cancer
  • Cisplatin
  • Collagen VI
  • Endotrophin
  • Thiazolidinediones

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. / Park, Jiyoung; Morley, Thomas S.; Scherer, Philipp E.

In: EMBO Molecular Medicine, Vol. 5, No. 6, 06.2013, p. 935-948.

Research output: Contribution to journalArticle

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