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The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism

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...

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Autores principales: 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, Han, Baek-Soo, Lee, Sang Chul, Hwang, Geum-Sook, Lee, Eun-Woo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10504358/
https://www.ncbi.nlm.nih.gov/pubmed/37714840
http://dx.doi.org/10.1038/s41467-023-41462-9
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author 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
Han, Baek-Soo
Lee, Sang Chul
Hwang, Geum-Sook
Lee, Eun-Woo
author_facet 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
Han, Baek-Soo
Lee, Sang Chul
Hwang, Geum-Sook
Lee, Eun-Woo
author_sort Oh, Mihee
collection PubMed
description 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.
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spelling pubmed-105043582023-09-17 The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism 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 Han, Baek-Soo Lee, Sang Chul Hwang, Geum-Sook Lee, Eun-Woo Nat Commun Article 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. Nature Publishing Group UK 2023-09-15 /pmc/articles/PMC10504358/ /pubmed/37714840 http://dx.doi.org/10.1038/s41467-023-41462-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Han, Baek-Soo
Lee, Sang Chul
Hwang, Geum-Sook
Lee, Eun-Woo
The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
title The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
title_full The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
title_fullStr The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
title_full_unstemmed The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
title_short The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
title_sort lipoprotein-associated phospholipase a2 inhibitor darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10504358/
https://www.ncbi.nlm.nih.gov/pubmed/37714840
http://dx.doi.org/10.1038/s41467-023-41462-9
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