Endogenous
fatty acid metabolism is crucial to maintain the
cancer cell malignant phenotype. Lipogenesis is regulated by the
enzyme fatty acid synthase (FASN); and breakdown of
fatty acids is regulated by
carnitine palmitoyltransferase-1 (
CPT-I). FASN is highly expressed in
breast cancer and most common human
carcinomas. Several compounds can inhibit FASN, although the degree of specificity of this inhibition has not been addressed. We have tested the effects of C75 and (-)-epigallocatechin-3-gallate (EGCG) on
fatty acid metabolism pathways, cellular proliferation, induction of apoptosis and cell signalling in human
breast cancer cells. Our results show that C75 and EGCG had comparable effects in blocking FASN activity. Treating
cancer cells with EGCG or C75 induced apoptosis and caused a decrease in the active forms of
oncoprotein HER2, AKT and ERK1/2 to a similar degree. We observed, in contrast, marked differential effects between C75 and EGCG on the
fatty acid oxidation pathway. While EGCG had either no effect or a moderate reduction in
CPT-I activity, C75 stimulated
CPT-I activity (up to 129%), even in presence of inhibitory levels of
malonyl-CoA, a potent inhibitor of the
CPT-I
enzyme. Taken together, these findings indicate that pharmacological inhibition of FASN occurs uncoupled from the stimulation of
CPT-I with EGCG but not with C75, suggesting that EGCG might be free of the
CPT-I related in vivo
weight-loss that has been associated with C75. Our results establish EGCG as a potent and specific inhibitor of
fatty acid synthesis (FASN), which may hold promise as a target-directed anti-
cancer drug.