alpha(v) integrins regulate cell proliferation through integrin-linked kinase (ILK) in ovarian cancer cells.
Integrins regulate both adhesion and signaling processes involved in proliferation and survival. alpha(v)beta(3) and alpha(v)beta(5) integrins have been shown to mediate cell adhesion and migration. Here we used human ovarian cancer cell lines (IGROV1, SKOV-3) that express alpha(v)beta(3) and alpha(v)beta(5) to study their role in cell proliferation and the signaling pathways involved. We found that alpha(v) integrins regulate cell proliferation through activation of integrin-linked kinase (ILK). An anti-alpha(v)-blocking antibody specifically inhibits the growth of IGROV1 and SKOV-3. The inhibition of cell proliferation involves alpha(v)beta(3) in IGROV1 cells, and both alpha(v)beta(3) and alpha(v)beta(5) in SKOV-3 cells. The reduced growth rate induced by alpha(v) integrin blockade is linked in both cell lines to G1/S cell cycle arrest. alpha(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-alpha(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 alpha(v) integrins regulate ovarian cancer cell proliferation through ILK.
Cruet-Hennequart
Séverine
S
British Columbia Cancer Agency, Jack Bell Research Centre, British Columbia, Canada.
Maubant
Sylvie
S
Luis
José
J
Gauduchon
Pascal
P
Staedel
Cathy
C
Dedhar
Shoukat
S
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099200:Scaffold Protein ILK
D039564:Integrin alphaV; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D000099200:Scaffold Protein ILK; C494918:AKT1 protein, human; C494929:PTEN protein, human