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

Background: 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. Results: We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface av beta 3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a beta 1 integrin-mediated pathway. We demonstrate that suppression of beta 1 integrin expression, in beta 3 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 beta 1 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 beta 3 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 beta 3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of beta 1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a beta 1 integrin-mediated pathway, increases paclitaxel sensitivity. Conclusions: Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a beta 3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.