WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells

Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC). However, the underlying molecular mechanisms are largely unknown. Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate e...

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Bibliographic Details
Published in:	Oncogene Vol. 32; no. 3; pp. 375 - 387
Main Authors:	Yuan, G, Regel, I, Lian, F, Friedrich, T, Hitkova, I, Hofheinz, R D, Ströbel, P, Langer, R, Keller, G, Röcken, C, Zimmermann, W, Schmid, R M, Ebert, M P A, Burgermeister, E
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 17-01-2013 Nature Publishing Group
Subjects:	5-Fluorouracil 631/67/1059/2326 631/67/1059/99 631/92/609 692/699/67/1504/1829 Adult Aged Aged, 80 and over Animal models Animals Anthracycline Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols Apoptosis Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Cancer Cancer therapies catenin Caveolae Caveolin 1 - metabolism caveolin-1 Cell Biology Cell death Cell Line, Tumor Chemoresistance Chemotherapy Cisplatin Conserved Sequence Doxorubicin Drug resistance Drug Resistance, Neoplasm - genetics Drug therapy Embryogenesis Epirubicin Epirubicin - pharmacology Female Gastric cancer Gene expression Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Glycoproteins Guanylate cyclase Health aspects Human Genetics Humans Integration Internal Medicine Male Medicine Medicine & Public Health Membrane proteins Mice Middle Aged Molecular modelling Mouse mammary tumor virus Oncology original-article Physiological aspects Plasma membranes Promoter Regions, Genetic - genetics Promoters scaffolds Signal Transduction - drug effects Stomach cancer Stomach Neoplasms - genetics Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Transcription Factor 4 Transcription Factors - metabolism Tumors Wnt protein Wnt Proteins - genetics Germany epirubicin stomach gastric cancer WNT caveolin
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Summary:	Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC). However, the underlying molecular mechanisms are largely unknown. Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate expression in the adult, in cancer. Here, we show expression of WNT6 in GC patient specimens, human GC cell lines and in a mouse model of GC. In human GC cells, WNT6 expression was enhanced by caveolin-1 (Cav1), a scaffold protein of plasma membrane caveolae. WNT6 knock-down and overexpression experiments demonstrated that WNT6 increased the resistance to apoptotic cell death induced by the anthracycline chemotherapeutics epirubicin (Epi) and doxorubicin (Dox). Epi increased the activity of the human WNT6 promoter through Cav1-dependent binding of β-catenin to the proximal WNT6 promoter. Epi increased both WNT6/Wnt6 and Cav1 expression in human GC cells and within the tumor area of a murine model of GC (CEA424-SV40 TAg). In GC patients, WNT6 expression was positively associated with the tumor stage and the nodal status, and inversely correlated with the response to ECF (Epi, cisplatin, 5-fluorouracil) chemotherapy. These results showed that WNT6 and Cav1 are upregulated by chemotherapeutics and enhance the resistance of GC cells to anthracycline drugs. Understanding the molecular mechanisms driving WNT6/Cav1-induced drug resistance will provide benefits in developing new therapies for GC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2012.40