β3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells

Molecular Cancer

Research

James D Brenton¹  Jillian Temple¹  David A Tumbarello² 

[1] Cancer Research UK, Cambridge Research Institute, Robinson Way, CB2 0RE, Cambridge, United Kingdom;Cancer Research UK, Cambridge Research Institute, Robinson Way, CB2 0RE, Cambridge, United Kingdom;Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, University of Cambridge, Hills Road, CB2 0XY, Cambridge, United Kingdom;

关键词: Chemotherapy;    Cell adhesion;    Ovarian cancer;    Integrin receptor;    Extracellular matrix;   

DOI  :  10.1186/1476-4598-11-36

 received in 2011-05-04, accepted in 2012-05-28,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundThe extracellular matrix (ECM) has a key role in facilitating the progression of ovarian cancer and we have shown recently that the secreted ECM protein TGFBI modulates the response of ovarian cancer to paclitaxel-induced cell death.ResultsWe have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αvβ3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a β1 integrin-mediated pathway. We demonstrate that suppression of β1 integrin expression, in β3 integrin-expressing ovarian cancer cells, increases adhesion to rTGFBI. In addition, Syndecan-1 and −4 expression is dispensable for adhesion to rTGFBI and loss of Syndecan-1 cooperates with the loss of β1 integrin to further enhance adhesion to rTGFBI. The RGD motif present in the carboxy-terminus of TGFBI is necessary, but not sufficient, for SKOV3 cell adhesion and is dispensable for adhesion of ovarian cancer cells lacking β3 integrin expression. In contrast to TGFBI, the carboxy-terminus of periostin, lacking a RGD motif, is unable to support adhesion of ovarian cancer cells. Suppression of β3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of β1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a β1 integrin-mediated pathway, increases paclitaxel sensitivity.ConclusionsTherefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a β3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.

【 授权许可】

Unknown   
© Tumbarello et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.