Page 132 - D. Cancer biology

[D. Cancer biology-82]

Polyunsaturated fatty acid biosynthesis pathway determines

ferroptosis sensitivity in gastric cancer

Ji-Yoon Lee¹˙²˙#, Miso Nam³˙#, Hye Young Son⁴˙#, Jong Woo Kim¹˙⁵, Min Wook Kim¹˙², Youngae Jung³,
Jaehoon Kim², Yong-Min Huh⁴˙⁶˙*, Geum-Sook Hwang³˙*, Sang Chul Lee¹˙⁵˙*, Eun-Woo Lee¹˙*

¹Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon

34141, Korea, ²Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST),
Daejeon 34141, Korea, ³Integrated Metabolomics Research Group, Korea Basic Science Institute (KBSI), Seoul
03760, Korea, ⁴Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03760, Korea,

⁵Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea, ⁶

MediBio-Informatics Research Center, Novomics Co., Ltd., Seoul 03760, Korea

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells can survive under
metabolic stress conditions by altering lipid metabolism, which can affect their sensitivity to ferroptosis. However,

the link between lipid metabolism and ferroptosis is not fully 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 upregulated

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 analysis revealed that intestinal-type GCs are defective in generating arachidonic acid (AA) and
adrenic acid (AdA) from linoleic acid. The supplementation of intestinal-type GCs with AA restores ferroptosis

sensitivity. These data reveal that the PUFA biosynthesis pathway plays an essential role in ferroptosis; thus, this
pathway can be considered a predictive marker for ferroptosis-mediated cancer therapy.