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

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Abstract
Integrins regulate both adhesion and signaling processes involved in proliferation and survival. αvβ3 and αvβ5 integrins have been shown to mediate cell adhesion and migration. Here we used human ovarian cancer cell lines (IGROV1, SKOV-3) that express αvβ3 and αvβ5 to study their role in cell proliferation and the signaling pathways involved. We found that αv integrins regulate cell proliferation through activation of integrin-linked kinase (ILK). An anti-αv-blocking antibody specifically inhibits the growth of IGROV1 and SKOV-3. The inhibition of cell proliferation involves αvβ3 in IGROV1 cells, and both αvβ3 and αvβ5 in SKOV-3 cells. The reduced growth rate induced by αv integrin blockade is linked in both cell lines to G1/S cell cycle arrest. αv 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 p27Kip1 expression. Overexpression of wild-type ILK rescued the phosphorylation of PKB/Akt on serine-473 in cells treated with anti-αv antibody. Inhibition of ILK by a pharmacological inhibitor results in inhibition of cell proliferation, PKB/Akt phosphorylation and increase of p27Kip1. These results demonstrate that αv integrins regulate ovarian cancer cell proliferation through ILK.