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 β(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 β(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 β(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 α(v)β(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 β(3) or upon pre-treatment with integrin β(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 β(3)-activating antibodies, AP7.4. CONCLUSION: Our data is the first to demonstrate a link between Akt1 activity and affinity modulation of integrin β(3) in the regulation of prostate cancer cell motility, transendothelial migration and chemotaxis to metastatic stimuli.