Regulation of podosomes by acetyl-CoA carboxylase

2898 Fatty acid synthesis is the process by which cells generate palmitate, a saturated 16 carbon fatty acid, from the carbohydrate derived precursors acetyl-CoA and malonyl-CoA. Apart from embryogenesis, fatty acid synthesis remains quiescent in normal tissue with the exception of liver and adipose. Conversely, tumor tissue relies on de novo fatty acid synthesis as its sole source of fatty acids, and is consequently upregulated in virtually all types of cancer. Because the fatty acid synthesis pathway is correlated with poor prognosis, aggressive disease, and metastasis, we hypothesize that this pathway is involved, at least in part, in the regulation of invasion and migration in tumor cells and in particular, in the regulation of podosomes, a dynamic membrane structure that is rich in F-actin and functions in adhesion and matrix degradation facilitating invasion and migration. NIH 3T3 fibroblasts transformed with c-src generate podosomes and, interestingly, also have increased levels of fatty acid synthesis compared to their non-transfected counterparts. Because of this, we reasoned that the fatty acid synthesis pathway may be involved in the formation of podosomes. Two nodes of the fatty acid synthesis pathway were targeted; the acetyl-CoA carboxylase (ACC) node and the fatty acid synthase (FASN) node. Pharmacologic inhibition of ACC (by 5-(tetradecyloxy)-2-furoic acid (TOFA)), but not FASN (by Cerulenin and C75) reduces podosome formation. This reduction also correlates with a decrease in cellular invasion and migration as well as a decrease in matrix metalloproteinases (MMP) 2 and 9 activities. Interestingly, treatment of transformed 3T3 cells with TOFA does not result in decreased clonogenic survival. Taken together, these data indicate a possible functional distinction between these two fatty acid synthesis enzymes and, more importantly, links the fatty acid synthesis pathway, at least in some part, to the regulation of podosomes and thus the process of invasion and migration.