ß3 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 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.


CONCLUSIONS
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.
Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, United Kingdom.
David A
DA
Tumbarello
Jillian
J
Temple
James D
JD
Brenton
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000099222:betaIG-H3 Protein
D000972:Antineoplastic Agents, Phytogenic; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D039661:Integrin beta3; D009842:Oligopeptides; D017239:Paclitaxel; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D053668:Syndecan-1; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C512835:POSTN protein, human; C047981:arginyl-glycyl-aspartic acid