Oh_2023_Nat.Commun_14_5728

Reference

Title : The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism - Oh_2023_Nat.Commun_14_5728
Author(s) : Oh M , Jang SY , Lee JY , Kim JW , Jung Y , Kim J , Seo J , Han TS , Jang E , Son HY , Kim D , Kim MW , Park JS , Song KH , Oh KJ , Kim WK , Bae KH , Huh YM , Kim SH , Han BS , Lee SC , Hwang GS , Lee EW
Ref : Nat Commun , 14 :5728 , 2023
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.

PubMedSearch : Oh_2023_Nat.Commun_14_5728
PubMedID: 37714840

Related information

Inhibitor Darapladib

Citations formats

Oh M, Jang SY, Lee JY, Kim JW, Jung Y, Kim J, Seo J, Han TS, Jang E, Son HY, Kim D, Kim MW, Park JS, Song KH, Oh KJ, Kim WK, Bae KH, Huh YM, Kim SH, Han BS, Lee SC, Hwang GS, Lee EW (2023)
The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
Nat Commun 14 :5728

Oh M, Jang SY, Lee JY, Kim JW, Jung Y, Kim J, Seo J, Han TS, Jang E, Son HY, Kim D, Kim MW, Park JS, Song KH, Oh KJ, Kim WK, Bae KH, Huh YM, Kim SH, Han BS, Lee SC, Hwang GS, Lee EW (2023)
Nat Commun 14 :5728