Darapladib, an inhibitor of Lp-PLA2, sensitises cancer cells to ferroptosis by remodelling lipid metabolism

ABSTRACT: Arachidonic and adrenic acids in the membrane play key roles in ferroptosis, but how these fatty acids are manipulated in cells is largely unknown. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen revealed that darapladib, an inhibitor of Lp-PLA2, synergistically induced ferroptosis in the presence of GPX4 inhibitors. Notably, darapladib was able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, Lp-PLA2 was located in the membrane and cytoplasm and suppressed ferroptosis, suggesting the critical role of intracellular Lp-PLA2. Lipidomic analysis showed that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriched phosphatidylethanolamine (PE) species and reduced lysophosphatidylethanolamine (lysoPE) species. Moreover, combination treatment with darapladib and PACMA31, a GPX4 inhibitor, efficiently inhibited 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.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Seoyoung Jang  

LAB HEAD: Geum-Sook Hwang

PROVIDER: PXD044002 | Pride | 2023-10-24

REPOSITORIES: Pride