한빛사 논문
- 조회322
Mihee Oh # 1, Seo Young Jang # 2, Ji-Yoon Lee # 3, Jong Woo Kim 3 4, Youngae Jung 2, Jiwoo Kim 5 6, Jinho Seo 7, Tae-Su Han 8, Eunji Jang 9, Hye Young Son 10 11, Dain Kim 2 12, Min Wook Kim 3, Jin-Sung Park 13, Kwon-Ho Song 14, Kyoung-Jin Oh 3 4, Won Kon Kim 3 4, Kwang-Hee Bae 3 4, Yong-Min Huh 9 10 11, Soon Ha Kim 13, Doyoun Kim 5, Baek-Soo Han 15 16 * 17, Sang Chul Lee 18 *, Geum-Sook Hwang 19 20 *, Eun-Woo Lee 21 22 23 *
1Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
2Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, 03759, Korea.
3Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
4Department of Functional Genomics, University of Science and Technology (UST), Daejeon, 34141, Korea.
5Therapeutics and Biotechnology Department, Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Korea.
6Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 305-764, Korea.
7Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
8Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
9MediBio-Informatics Research Center, Novomics Co., Ltd., Seoul, Korea.
10YUHS-KRIBB Medical Convergence Research Institute, Seoul, 03722, Korea.
11Department of Radiology, College of Medicine, Yonsei University, Seoul, 03722, Korea.
12Department of Life Science, Ewha Womans University, Seoul, 03760, Korea.
13MitoImmune Therapeutics Inc., Seoul, 06123, Korea.
14Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu, 42472, Korea.
15Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
16Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
17Department of Functional Genomics, University of Science and Technology (UST), Daejeon, 34141, Korea.
18Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
19Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, 03759, Korea.
20College of Pharmacy, Chung-Ang University, Seoul, 06974, Korea.
21Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
22Department of Functional Genomics, University of Science and Technology (UST), Daejeon, 34141, Korea.
23School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea.
#Contributed equally.
*Corresponding author: correspondence to Baek-Soo Han, Sang Chul Lee, Geum-Sook Hwang or Eun-Woo Lee
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.
논문정보
- Research article
- 2023년 09월 (BRIC 등록일 2023-09-18)
- 국내 연구진
- 생명과학 > 노화/암생물학
댓글 작성 로그인
팝업 닫기관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
