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- 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; Kim, Jiwoo; Seo, Jinho; Han, Tae-Su; Jang, Eunji; Son, Hye Young; Kim, Dain; Kim, Min Wook; Park, Jin-Sung; Song, Kwon-Ho; Oh, Kyoung-Jin; Kim, Won Kon; Bae, Kwang-Hee; Huh, Yong-Min; Kim, Soon Ha; Kim, Doyoun
- 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. Ferroptosis is an iron-dependent cell death mechanism that is emerging as a target for cancer therapy. Here, the authors find that lipoprotein-associated phospholipase A2 modulates ferroptosis resistance by controlling phospholipid metabolism.
- Subjects
PHOSPHOLIPASE A2; LIPID metabolism; CANCER cells; METABOLIC regulation; ARACHIDONIC acid; PHOSPHOLIPASES; CYTOPLASM
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41462-9