Targeting ILK and β4 integrin abrogates the invasive potential of ovarian cancer

Abstract

Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signalling pathways. The purpose of our study is to determine whether deletion of β1 and β4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of β1 and β4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We further assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays. We also investigated effect of shRNA-mediated depletion on in vivo growth of ovarian cancer xenografts in nude mice. Overexpression of β4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppressed ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that depletion of these inhibited phosphorylation of p-Ser473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduced expression of MMP-2 and MMP-9. By contrast, depletion of those induced caspase-3 activation. In conclusion, targeting β4 integrin combined with ILK can abrogate the invasive potential in ovarian cancer.