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 |
Inhibitor | Darapladib |
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