αv integrins regulate cell proliferation through integrin-linked kinase (ILK) in ovarian cancer cells

Abstract

Integrins regulate both adhesion and signaling processes involved in proliferation and survival. _v3 and _v5 integrins have been shown to mediate cell adhesion and migration. Here we used human ovarian cancer cell lines (IGROV1, SKOV-3) that express _v3 and _v5 to study their role in cell proliferation and the signaling pathways involved. We found that _v integrins regulate cell proliferation through activation of integrin-linked kinase (ILK). An anti-_v-blocking antibody specifically inhibits the growth of IGROV1 and SKOV-3. The inhibition of cell proliferation involves _v3 in IGROV1 cells, and both _v3 and _v5 in SKOV-3 cells. The reduced growth rate induced by _v integrin blockade is linked in both cell lines to G1/S cell cycle arrest. _v integrin blockade by neutralizing antibody as well as cyclic-RGD peptide caused an inhibition of ILK activity and phosphorylation of PKB/Akt on serine-473 but not on threonine-308, and was accompanied by an increase in p27^Kip1 expression. Overexpression of wild-type ILK rescued the phosphorylation of PKB/Akt on serine-473 in cells treated with anti-_v antibody. Inhibition of ILK by a pharmacological inhibitor results in inhibition of cell proliferation, PKB/Akt phosphorylation and increase of p27^Kip1. These results demonstrate that _v integrins regulate ovarian cancer cell proliferation through ILK.