ADAM15 decreases integrin αvβ3/vitronectin-mediated ovarian cancer cell adhesion and motility in an RGD-dependent fashion

Abstract

We have recently described that integrin αvβ3 upon interaction with its major extracellular matrix ligand vitronectin induces adhesion, motility, and proliferation of human ovarian cancer cells. Due to the important function of αvβ3 in cancer cell biology, it has been the effort of many scientific approaches to specifically target αvβ3-mediated cell adhesion and tumorbiological effects arising thereof by synthetic integrin antagonists. More recently, proteins of the ADAM family have been recognized as naturally occurring integrin ligands. Among those, human ADAM15 which encompasses the integrin binding RGD motif was shown to interact with integrin αvβ3. Thus, we investigated in human ovarian OV-MZ-6 cancer cells, expressing both ADAM15 and αvβ3, whether ADAM15 might affect αvβ3-mediated tumorbiological effects. We stably (over)expressed ADAM15 or its extracellular domain in OV-MZ-6 cells as well as respective ADAM15 mutants containing the tripeptide SGA instead of RGD. Cells (over)expressing ADAM15-RGD exhibited a significantly reduced αvβ3-mediated adhesion to vitronectin. Also, a significant time-dependent decline in numbers of cells cultivated on vitronectin was noticed. This effect was found to be rather due to impaired αvβ3-mediated cell adhesion than decreased cell proliferation rates, since de novo DNA synthesis was not significantly altered by elevated ADAM15 expression. Moreover, a substantially decreased random cellular motility was noticed as a function of ADAM15 encompassing an intact RGD motif. In conclusion, our results point to a physiological role of ADAM15 as a natural binding partner of integrin αvβ3 thereby loosening tumor cell adhesion to the underlying matrix and regulating tumor cell migration and invasion.