Increased lipogenesis is a hallmark of a wide variety of
cancers and is under intense investigation as potential
antineoplastic target. Although brisk lipogenesis is observed in the presence of exogenous
lipids, evidence is mounting that these
lipids may adversely affect the efficacy of inhibitors of lipogenic pathways. Therefore, to fully exploit the therapeutic potential of
lipid synthesis inhibitors, a better understanding of the interrelationship between de novo
lipid synthesis and exogenous
lipids and their respective role in
cancer cell proliferation and therapeutic response to lipogenesis inhibitors is of critical importance. Here, we show that the proliferation of various
cancer cell lines (PC3M, HepG2, HOP62 and T24) is attenuated when cultured in
lipid-reduced conditions in a cell line-dependent manner, with PC3M being the least affected. Interestingly, all cell lines--lipogenic (PC3M, HepG2, HOP62) as well as non-lipogenic (T24)--raised their lipogenic activity in these conditions, albeit to a different degree. Cells that attained the highest lipogenic activity under these conditions were best able to cope with
lipid reduction in term of proliferative capacity. Supplementation of the medium with
very low density lipoproteins,
free fatty acids and
cholesterol reversed this activation, indicating that the mere lack of
lipids is sufficient to activate de novo lipogenesis in
cancer cells. Consequently,
cancer cells grown in
lipid-reduced conditions became more dependent on de novo
lipid synthesis pathways and were more sensitive to inhibitors of lipogenic pathways, like
Soraphen A and
Simvastatin. Collectively, these data indicate that limitation of access to exogenous
lipids, as may occur in intact
tumors, activates de novo lipogenesis is
cancer cells, helps them to thrive under these conditions and makes them more vulnerable to lipogenesis inhibitors. These observations have important implications for the design of new
antineoplastic strategies targeting the
cancer cell's lipid metabolism.