Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production

The Akt/protein kinase B (PKB) serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. Here, we demon strate for the first time a major role of Akt/PKB in the cell invasion prop erties of the highly metastatic cell line HT1080. Using confocal microscopi c analyses of live samples, we found Akt/PKB to be localized in the leading edge membrane area of migrating HT1080 cells. This localization was depend ent on phosphoinositide 3-kinase and required the lipid binding ability of the phosphoinositide binding pleckstrin homology domain of Akt/PKB. We exam ined the possible function of Akt/PKB in HT1080 invasion. Surprisingly, Akt /PKB potently promoted HT1080 invasion, by increasing cell motility and mat rix metalloproteinase-9 (MMP-9) production, in a manner highly dependent on its kinase activity and membrane-translocating ability. The increase in MM P-9 production was mediated by activation of nuclear factor-kappaB transcri ptional activity by Akt/PKB. However, Akt/PKB did not affect the cell-cell or cell-matrix adhesion properties of HT1080. Our findings thus establish A kt/PKB as a major factor in the invasive abilities of cancer cells.