Akt Regulates Raf/Mek/Erk Cascade, Vegf And Matrix Metalloproteinase (Mmp) Expression, And Malignant Characteristics Of Nsclc Cells

Phosphatidylinositol 3‐kinase (PI3K)/Akt‐mediated regulation of Raf/MEK/ERK activity has been identified in immune cells, the central nervous system, and skeletal muscle; however, an interaction has not been established in non‐small cell lung carcinoma (NCSLC).We examined Akt‐Raf cross‐talk in NSCLC by immunofluorescence (IF), co‐immunoprecipitation (co‐IP) and manipulation of target gene expression. While transiently expressed PI3K and Akt decreased MEK/ERK activity, functional‐deficient PI3K and Akt elevated MEK/ERK activity, suggesting that the PI3K/Akt pathway negatively regulates MEK/ERK activity in NSCLC. IF revealed Akt co‐localization with Raf but not Ras or ERK. Additionally, co‐IP confirmed an increased Akt‐Raf association and enriched cytoplasmic Raf following Akt activation. PI3K/Akt, but not MEK/ERK signaling, appears to be essential for maintaining malignant characteristics of NSCLC cells. Furthermore, both the promoter activity and protein levels of VEGF and MMP‐2 showed a PI3K/Akt‐, but not MEK/ERK‐dependent, pattern. Moreover, interference with PI3K/Akt function, but not that of MEK/ERK, decreased cell viability. These data reveal regulation of Raf/MEK/ERK by the PI3K/Akt pathway, a novel finding in NSCLC. This finding is highly relevant to understanding the pathogenesis and behavior of NSCLC and may be of value for future therapeutic directions. Research support: Penn State University College of Medicine Department of Pathology.