학술논문
The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
Document Type
article
Author
Mihee Oh; Seo Young Jang; Ji-Yoon Lee; Jong Woo Kim; Youngae Jung; Jiwoo Kim; Jinho Seo; Tae-Su Han; Eunji Jang; Hye Young Son; Dain Kim; Min Wook Kim; Jin-Sung Park; Kwon-Ho Song; Kyoung-Jin Oh; Won Kon Kim; Kwang-Hee Bae; Yong-Min Huh; Soon Ha Kim; Doyoun Kim; Baek-Soo Han; Sang Chul Lee; Geum-Sook Hwang; Eun-Woo Lee
Source
Nature Communications, Vol 14, Iss 1, Pp 1-17 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
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.