title: Fatty acid synthase inhibitor cerulenin inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Na Young
authors.initials: NY
authors.lastname: Jeong
authors.forename: Jee Suk
authors.initials: JS
authors.lastname: Lee
authors.forename: Ki Soo
authors.initials: KS
authors.lastname: Yoo
authors.forename: Soojung
authors.initials: S
authors.lastname: Oh
authors.forename: Eunok
authors.initials: E
authors.lastname: Choe
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Park
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004357:Drug Synergism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D059004:Topoisomerase I Inhibitors; D002569:Cerulenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077146:Irinotecan; D064429:Fatty Acid Synthases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin