Regulation of cancer cell metastatic properties by Akt

Abstract

The Akt serine/threonine kinase is well known as an important mediator of multiple cell survival signaling pathways. Here, I demonstrate for the first time a major role of Akt in the metastatic properties of the highly metastatic cell line, HT1080. Using live confocal microscopic analyses, I found Akt to be localized in the leading edge membrane area of migrating HT1080 cells. This localization was phosphoinositide-3 kinase (PI3K)-dependent and required the lipid binding ability of the phosphoinositides-binding pleckstrin homology (PH) domain of Akt. I examined the possible function of Akt in HT1080 invasion. Surprisingly, Akt potently promoted HT1080 invasion, by increasing cell motility and matrix metalloproteinase-9 production, in a manner highly dependent on its kinase activity and membrane-translocating ability. The increase in matrix metalloproteinase-9 (MMP-9) production was mediated by activation of NF-$\kappa$B transcriptional activity by Akt. However, Akt did not affect the cell-cell or cell-matrix adhesion properties of HT1080. Collectively, my findings establish Akt as a major factor in the metastatic abilities of cancer cells.