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

Author

Listed:
  • Mihee Oh

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Seo Young Jang

    (Western Seoul Center, Korea Basic Science Institute)

  • Ji-Yoon Lee

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Jong Woo Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology (UST))

  • Youngae Jung

    (Western Seoul Center, Korea Basic Science Institute)

  • Jiwoo Kim

    (Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT)
    Chungnam National University)

  • Jinho Seo

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Tae-Su Han

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Eunji Jang

    (Novomics Co., Ltd.)

  • Hye Young Son

    (YUHS-KRIBB Medical Convergence Research Institute
    Yonsei University)

  • Dain Kim

    (Western Seoul Center, Korea Basic Science Institute
    Ewha Womans University)

  • Min Wook Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Jin-Sung Park

    (MitoImmune Therapeutics Inc.)

  • Kwon-Ho Song

    (Daegu Catholic University School of Medicine)

  • Kyoung-Jin Oh

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology (UST))

  • Won Kon Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology (UST))

  • Kwang-Hee Bae

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology (UST))

  • Yong-Min Huh

    (Novomics Co., Ltd.
    YUHS-KRIBB Medical Convergence Research Institute
    Yonsei University)

  • Soon Ha Kim

    (MitoImmune Therapeutics Inc.)

  • Doyoun Kim

    (Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT))

  • Baek-Soo Han

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology (UST))

  • Sang Chul Lee

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Geum-Sook Hwang

    (Western Seoul Center, Korea Basic Science Institute
    Chung-Ang University)

  • Eun-Woo Lee

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology (UST)
    Sungkyunkwan University)

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.

Suggested Citation

  • 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 & Kyoun, 2023. "The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41462-9
    DOI: 10.1038/s41467-023-41462-9
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