Akt1 mediates prostate cancer cell microinvasion and chemotaxis to metastatic stimuli via integrin β3 affinity modulation

BACKGROUND: Activation of Akt and increased expression of integrin beta(3) are the two most important changes that have been linked to the attainment of metastatic potential by prostate cancer cells. However, a direct link between Akt activity and inside-out activation of integrin beta(3) in mediating prostate cancer cell metastatic properties is not established. METHODS: Using functional and biochemical approaches, we examined the role of Akt1 in the affinity modulation of integrin beta(3) in prostate cancer cells. RESULTS: Although expression of murine TRAMP and human PC3 cells with constitutively active Akt1 (CA-Akt1) enhanced their affinity for integrin alpha(v)beta(3) specific ligands and motility on various extracellular matrix proteins, the reverse was observed with the expression of dominant-negative Akt1 (DN-Akt1). Although enhanced motility and transendothelial migration of CA-Akt1-expressing cells were blunted by co-expression with DN-integrin beta(3) or upon pre-treatment with integrin beta(3)-blocking antibodies (LM 609), impaired motility and transendothelial migration of DN-Akt1-expressing cells were rescued by pre-treatment of prostate cancer cells with integrin beta(3)-activating antibodies, AP7.4. CONCLUSION: Our data is the first to demonstrate a link between Akt1 activity and affinity modulation of integrin beta(3) in the regulation of prostate cancer cell motility, transendothelial migration and chemotaxis to metastatic stimuli. British Journal of Cancer (2012) 107, 713-723. doi:10.1038/bjc.2012.295 www.bjcancer.com Published online 5 July 2012 (C) 2012 Cancer Research UK