Article

ß3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells.

Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom. .
Molecular Cancer (impact factor: 3.99). 05/2012; 11:36. DOI:10.1186/1476-4598-11-36 pp.36
Source: PubMed

ABSTRACT The 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.
We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αvß3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a ß1 integrin-mediated pathway. We demonstrate that suppression of ß1 integrin expression, in ß3 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 ß1 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 ß3 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 ß3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of ß1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a ß1 integrin-mediated pathway, increases paclitaxel sensitivity.
Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a ß3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.

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Keywords

-4 expression
 
cell surface αvß3 integrin heterodimer
 
extracellular environment
 
extracellular matrix
 
fibronectin expression
 
increases adhesion
 
ovarian cancer cells
 
paclitaxel-induced cell death
 
secreted ECM protein TGFBI modulates
 
SKOV3 cell adhesion
 
support adhesion
 
Syndecan-1 cooperates
 
TGFBI expression stimulates
 
TGFBI paralogue
 
TGFBI signaling
 
ß1 integrin
 
ß1 integrin expression
 
ß1 integrin-mediated pathway
 
ß3 integrin
 
ß3 integrin expression
 

David A Tumbarello