Fatty acid synthase (FASN) is overexpressed in a wide variety of human
cancers, making it an attractive target for anticancer
therapy. One of the most widely used inhibitors of FASN,
cerulenin, is a
natural product of Cephalosporium caerulens.
Cerulenin is selectively toxic to human
cancer cells in vitro. However, the mechanism by which FASN inhibition causes apoptosis in
tumor cells remains unclear. Because of the widespread clinical interest in combining
cerulenin with other chemotherapeutic agents, we performed this study to gain insight into the downstream effects of FASN inhibition that lead to apoptosis. Here, we observed the increased antitumor effect of
cerulenin when combined with the
topoisomerase inhibitor SN-38. We identified
topoisomerase I as a potential mediator of
cerulenin-induced apoptosis, possibly by upregulating intracellular polyunsaturation. Finally, we show that suppressing
topoisomerase I catalytic activity results in synergistic effects between
cerulenin and
LY294002. Our results suggest that
topoisomerase I could participate in
cerulenin-induced apoptosis by upregulating intracellular polyunsaturation. These results will help determine the molecular basis of the
cerulenin and
SN-38 drug combination. Further investigation of this pathway will provide new insight into
cancer cell metabolism and may aid in the design of additional
cancer chemotherapeutic agents.