Epithelial-Mesenchymal Transition Markers and HER3 Expression Are Predictors of Elisidepsin Treatment Response in Breast and Pancreatic Cancer Cell Lines
Teixidó, Cristina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Marés, Roso (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Aracil, Miguel (Pharmamar, Madrid, Spain)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron)
Hernandez-Losa, Javier (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Fecha:	2013
Resumen:	Elisidepsin (elisidepsin trifluoroacetate, Irvalec®, PM02734) is a new synthetic depsipeptide, a result of the PharmaMar Development Program that seeks synthetic products of marine origin-derived compounds. Elisidepsin is a drug with antiproliferative activity in a wide range of tumors. In the present work we studied and characterized the mechanisms associated with sensitivity and resistance to elisidepsin treatment in a broad panel of tumor cell lines from breast and pancreas carcinomas, focusing on different factors involved in epithelial-mesenchymal transition (EMT) and the use of HER family receptors in predicting the in vitro drug response. Interestingly, we observed that the basal protein expression levels of EMT markers show a significant correlation with cell viability in response to elisidepsin treatment in a panel of 12 different breast and pancreatic cancer cell lines. In addition, we generated three elisidepsin treatment-resistant cell lines (MCF-7, HPAC and AsPC-1) and analyzed the pattern of expression of different EMT markers in these cells, confirming that acquired resistance to elisidepsin is associated with a switch to the EMT state. Furthermore, a direct correlation between basal HER3 expression and sensitivity to elisidepsin was observed; moreover, modulation of HER3 expression levels in different cancer cell lines alter their sensitivities to the drug, making them more resistant when HER3 expression is downregulated by a HER3-specific short hairpin RNA and more sensitive when the receptor is overexpressed. These results show that HER3 expression is an important marker of sensitivity to elisidepsin treatment.
Nota:	Altres ajuts: This work has been partially funded by Pharmamar Company and by CENIT grant (CEN-2009-1016). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	PloS one, Vol. 8 (january 2013) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0053645
PMID: 23320098

12 p, 6.4 MB

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