title: Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours.
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.
authors: Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: Jiyoung
authors: J
authors: Park
authors: Thomas S
authors: TS
authors: Morley
authors: Philipp E
authors: PE
authors: Scherer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D024142:Collagen Type VI / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D024142:Collagen Type VI; D010446:Peptide Fragments; D045162:Thiazolidinediones; C584135:endotrophin; D002945:Cisplatin
references: Oncotarget. 2012 Dec;3(12):1487-8
references: 23455368
references: Oncogene. 2002 Mar 28;21(14):2171-80
references: 11948400
references: Mol Cancer Ther. 2010 Dec;9(12):3221-32
references: 21159608
references: Am J Pathol. 2010 Dec;177(6):3133-44
references: 21056997
references: Breast Cancer Res Treat. 2003 Jun;79(3):391-7
references: 12846423
references: Cancer Invest. 2007;25(7):542-9
references: 17952737
references: Cancer Res. 2001 Aug 15;61(16):6213-8
references: 11507074
references: Oncogene. 2012 Apr 12;31(15):1869-83
references: 21892204
references: J Clin Invest. 2005 May;115(5):1163-76
references: 15841211
references: BMC Cancer. 2012 Mar 19;12:91
references: 22429801
references: Oncol Rep. 2005 Oct;14(4):925-32
references: 16142353
references: Cancer Res. 1998 Apr 1;58(7):1486-93
references: 9537252
references: Hum Mol Genet. 1998 Dec;7(13):2135-40
references: 9817932
references: Cancer J. 2002 Sep-Oct;8(5):395-9
references: 12416897
references: Biochem J. 2012 Jan 15;441(2):541-52
references: 22187935
references: Oncol Rep. 2012 Apr;27(4):1027-34
references: 22245869
references: Cancer Res. 2009 Jul 15;69(14):5820-8
references: 19584296
references: Cancer Res. 2011 Feb 1;71(3):1019-28
references: 21148071
references: Clin Cancer Res. 2008 Oct 15;14(20):6478-86
references: 18927287
references: Ann Oncol. 2008 Nov;19(11):1847-52
references: 18567607
references: Clin Breast Cancer. 2004 Dec;5(5):371-6
references: 15585076
references: Mol Cell. 1998 Feb;1(3):465-70
references: 9660931
references: Annu Rev Biochem. 2008;77:289-312
references: 18518822
references: BMC Cancer. 2009 Apr 08;9:107
references: 19356226
references: Oncogene. 2011 Jun 16;30(24):2697-706
references: 21339741
references: J Cell Biochem. 2011 Oct;112(10):2850-64
references: 21618587
references: Cancer Cell. 2003 Apr;3(4):377-86
references: 12726863
references: Nat Rev Cancer. 2007 Aug;7(8):573-84
references: 17625587
references: Lancet Oncol. 2001 Jul;2(7):437-42
references: 11905738
references: Clin Cancer Res. 2008 Sep 1;14(17):5555-64
references: 18765548
references: J Clin Invest. 2012 Nov;122(11):4243-56
references: 23041627
references: Clin Cancer Res. 2011 Apr 15;17(8):2350-60
references: 21220476
references: Nat Med. 1999 Jun;5(6):662-8
references: 10371505
references: Cancer Ther. 2008;6(A):25-34
references: 19079765
references: Mol Cell Biol. 1992 Mar;12(3):954-61
references: 1312220
references: Cancer. 2004 Oct 1;101(7):1569-74
references: 15468186
references: Genes Dev. 2004 Mar 1;18(5):528-40
references: 15037548
references: Cancer Cell. 2007 May;11(5):395-406
references: 17482130
references: Mol Cell Biol. 2009 Mar;29(6):1575-91
references: 19114551
references: Cancer Res. 2000 May 1;60(9):2497-503
references: 10811131
references: Int J Biol Markers. 2003 Jul-Sep;18(3):162-9
references: 14535585
references: Clin Cancer Res. 2009 May 15;15(10):3265-76
references: 19447867