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Fatty acid synthase inhibitor cerulenin inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis

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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.

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Acknowledgments

This study was supported by a National Research Foundation of Korea Grant funded by the Korean Government (2011 0001262).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan, Republic of Korea

    Na Young Jeong, Jee Suk Lee, Ki Soo Yoo & Young Hyun Yoo

  2. Department of Food and Nutrition, Inha University, Yonghyundong, Namku, Incheon, Republic of Korea

    Soojung Oh & Eunok Choe

  3. Department of Pharmacology, Dong-A University College of Medicine, Busan, Republic of Korea

    Hye-Jeong Lee

  4. Department of Oral Anatomy and Cell Biology, Pusan National University College of Dentistry, Yangsan, Republic of Korea

    Bong Soo Park

  5. Department of Biochemistry and Research Institute of Oriental Medicine, Dongeui University College of Oriental Medicine, Busan, Republic of Korea

    Yung Hyun Choi

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  1. Na Young Jeong
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10495_2012_776_MOESM1_ESM.tif

Supplementary material Fig. S1 a Molecular structure of cerulenin. b Synergism between cerulenin and SN-38. Additional cell lines (T98G, U373MG and Hep3B) were treated with 100 nM SN-38 alone, 25 µM cerulenin alone, or both for 48 h. Live cells were determined using a trypan blue exclusion assay after 48 h. c Immunofluorescent micrographs showing the sustained expression level of topoisomerase I. Cells were incubated with anti-human topoisomerase I antibody (Santa Cruz Biotechnology, Santa Cruz, CA) and then with FITC-conjugated secondary antibody. Fluorescent images were observed and analyzed under Zeiss LSM 510 laser-scanning confocal microscope (Zeiss, Goettingen, Germany). (TIFF 15368 kb)

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Jeong, N.Y., Lee, J.S., Yoo, K.S. et al. Fatty acid synthase inhibitor cerulenin inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis. Apoptosis 18, 226–237 (2013). https://doi.org/10.1007/s10495-012-0776-4

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