2. Academic Validation
  3. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

  • Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32433-32442. doi: 10.1073/pnas.2006828117.
Ji-Yoon Lee 1 2,  Miso Nam 3,  Hye Young Son 4,  Kwangbeom Hyun 1,  Seo Young Jang 3 5,  Jong Woo Kim 2 6,  Min Wook Kim 2,  Youngae Jung 3,  Eunji Jang 7,  Seon-Jin Yoon 8,  Jungeun Kim 7,  Jihye Kim 7,  Jinho Seo 9,  Jeong-Ki Min 5 10,  Kyoung-Jin Oh 2 6,  Baek-Soo Han 6 11,  Won Kon Kim 2 6,  Kwang-Hee Bae 2 6 12,  Jaewhan Song 13,  Jaehoon Kim 1,  Yong-Min Huh 14 7 12 15,  Geum-Sook Hwang 16 5,  Eun-Woo Lee 17,  Sang Chul Lee 17
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Korea.
  • 2 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141 Daejeon, Korea.
  • 3 Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, 03759 Seoul, Korea.
  • 4 Severance Biomedical Science Institute, Yonsei University College of Medicine, 03722 Seoul, Korea.
  • 5 Department of Chemistry and Nano Science, Ewha Woman's University, 03760 Seoul, Korea.
  • 6 Department of Functional Genomics, University of Science and Technology, 34141 Daejeon, Korea.
  • 7 MediBio-Informatics Research Center, Novomics Co., Ltd., 07217 Seoul, Korea.
  • 8 Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 03722 Seoul, Korea.
  • 9 Environmental Diseases Research Center, KRIBB, 34141 Daejeon, Korea.
  • 10 Biotherapeutics Translational Research Center, KRIBB, 34141 Daejeon, Korea.
  • 11 Biodefense Research Center, KRIBB, 34141 Daejeon, Korea.
  • 12 Yonsei University Health System (YUHS)-KRIBB Medical Convergence Research Institute, 03722 Seoul, Korea.
  • 13 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 03722 Seoul, Korea.
  • 14 Severance Biomedical Science Institute, Yonsei University College of Medicine, 03722 Seoul, Korea; [email protected] [email protected] [email protected] [email protected].
  • 15 Department of Radiology, Severance Hospital, Yonsei University College of Medicine, 03722 Seoul, Korea.
  • 16 Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, 03759 Seoul, Korea; [email protected] [email protected] [email protected] [email protected].
  • 17 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141 Daejeon, Korea; [email protected] [email protected] [email protected] [email protected].
PMID: 33288688 DOI: 10.1073/pnas.2006828117
Abstract

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to Ferroptosis. However, the association between lipid metabolism and Ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric Cancer cells (GCs), leading to Ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to Ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to Ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated Cancer therapy.

Keywords

ELOVL5; FADS1; arachidonic acid; ferroptosis; lipid peroxidation.

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