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The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
- Title
- The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
- Authors
- Oh; Mihee; Jang; Seo Young; Lee; Ji-Yoon; Kim; Jong Woo; Jung; Youngae; Jiwoo; Seo; Jinho; Han; Tae-Su; Eunji; Son; Hye Young; Dain; Min Wook; Park; Jin-Sung; Song; Kwon-Ho; Kyoung-Jin; Won Kon; Bae; Kwang-Hee; Huh; Yong-Min; Soon Ha; Doyoun; Baek-Soo; Sang Chul; Hwang; Geum-Sook; Eun-Woo
- Ewha Authors
- 황금숙
- SCOPUS Author ID
- 황금숙
- Issue Date
- 2023
- Journal Title
- Nature Communications
- ISSN
- 2041-1723
- Citation
- Nature Communications vol. 14, no. 1
- Publisher
- Nature Research
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment. © 2023, Springer Nature Limited.
- DOI
- 10.1038/s41467-023-41462-9
- Appears in Collections:
- 자연과학대학 > 화학·나노과학전공 > Journal papers
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