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抑制胶原 VI 的裂解产物内毒素可提高肿瘤对顺铂的敏感性。

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

机构信息

Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.

出版信息

EMBO Mol Med. 2013 Jun;5(6):935-48. doi: 10.1002/emmm.201202006. Epub 2013 Apr 30.

DOI:10.1002/emmm.201202006
PMID:23629957
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3779453/
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.

摘要

内抑肽是胶原 VIα3（COL6A3）的裂解产物。在这里，我们在乳腺肿瘤模型的背景下探讨了噻唑烷二酮（TZDs）、内抑肽和顺铂耐药之间的关系。COL6A3 水平在肿瘤中因顺铂暴露而增加。反过来，内抑肽导致顺铂耐药。通过使用 COL6 缺失（COL6(-/-)）小鼠或在野生型小鼠中给予 TZDs（导致内抑肽下调），可以绕过内抑肽的作用。这两种方法都通过抑制内抑肽诱导的上皮-间充质转化使肿瘤对顺铂敏感。在 COL6(-/-) 小鼠中，TZDs 对顺铂敏感性的有益影响减弱，而内抑肽(+)肿瘤对 TZD/顺铂联合治疗敏感。因此，TZDs 获得的化疗增敏作用是通过下调内抑肽来实现的。用内抑肽中和抗体联合顺铂治疗可完全抑制肿瘤异种移植物的生长。综上所述，内抑肽水平是 TZDs 与顺铂联合治疗有效性的一个强有力的预后标志物，内抑肽活性的中和显著改善了联合治疗的治疗反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/c77c19916a46/emmm0005-0935-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/c83c146ccaa2/emmm0005-0935-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/3e8c02906441/emmm0005-0935-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/973739dfb90b/emmm0005-0935-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/87157a6542fb/emmm0005-0935-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/0e8cdb6a04e8/emmm0005-0935-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/f4dcb14a5b97/emmm0005-0935-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/c77c19916a46/emmm0005-0935-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/c83c146ccaa2/emmm0005-0935-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/3e8c02906441/emmm0005-0935-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/973739dfb90b/emmm0005-0935-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/87157a6542fb/emmm0005-0935-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/0e8cdb6a04e8/emmm0005-0935-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/f4dcb14a5b97/emmm0005-0935-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2563/3779453/c77c19916a46/emmm0005-0935-f7.jpg

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EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer.EMT 转录因子 snail 和 slug 直接导致卵巢癌细胞对顺铂产生耐药性。
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