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

We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αv？3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a ？1 integrin-mediated pathway. We demonstrate that suppression of ？1 integrin expression, in ？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 ？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 ？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 ？3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of ？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 ？1 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 ？3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.