Activation of Fatty Acid Synthesis during Neoplastic Transformation: Role of Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase

Abstract

Activation of fatty acid synthase (FAS) expression and fatty acid synthesis is a common event in tumor cells from a variety of human cancers and is closely linked to malignant transformation and to tumor virulence in population studies of human cancer. We now show that, in contrast to nutritional regulation of lipogenesis in liver or adipose tissue, changes in fatty acid metabolism during in vitro transformation of the human mammary epithelial cell line MCF-10a are driven by increases in epidermal growth factor signaling, acting in major part through the mitogen-activated protein (MAP) kinase and phosphatidylinositol (PI) 3-kinase signaling cascades. H- ras transformation of MCF-10a cells resulted in upregulation of MAP kinase and PI 3-kinase signals, upregulation of sterol regulatory element binding protein 1 (SREBP-1) transcription factor levels, and upregulation of FAS expression and FA synthesis. Deletion of the major SREBP binding site from the FAS promoter abrogated transcription in transformed MCF-10a cells. Inhibitors of MAP and PI 3-kinases downregulated SREBP-1 levels and decreased transcription from the FAS promoter, reducing FAS expression and fatty acid synthesis in transformed MCF-10a cells and in MCF-7 and HCT116 carcinoma cells. H- ras transformation sensitized MCF-10a cells to the FAS inhibitors cerulenin and C-75. These results confirm an important role for SREBP-1 in neoplastic lipogenesis, and provide a likely basis for the linkage of upregulated fatty acid metabolism with neoplastic transformation and with tumor virulence, since MAP and PI 3-kinase signaling contributes to both.