Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Ji Yoon Lee; Miso Nam; Hye Young Son; Kwangbeom Hyun; Seo Young Jang; Jong Woo Kim; Min Wook Kim; Youngae Jung; Eunji Jang; Seon Jin Yoon; Jungeun Kim; Jihye Kim; Jinho Seo; Jeong Ki Min; Kyoung Jin Oh; Baek Soo Han; Won Kon Kim; Kwang Hee Bae; Jaewhan Song; Jaehoon Kim; Yong Min Huh; Geum Sook Hwang; Eun Woo Lee; Sang Chul Lee

doi:10.1073/pnas.2006828117

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Ji Yoon Lee, Miso Nam, Hye Young Son, Kwangbeom Hyun, Seo Young Jang, Jong Woo Kim, Min Wook Kim, Youngae Jung, Eunji Jang, Seon Jin Yoon, Jungeun Kim, Jihye Kim, Jinho Seo, Jeong Ki Min, Kyoung Jin Oh, Baek Soo Han, Won Kon Kim, Kwang Hee Bae, Jaewhan Song, Jaehoon KimYong Min Huh, Geum Sook Hwang, Eun Woo Lee, Sang Chul Lee

Research output: Contribution to journal › Article › peer-review

88 Citations (Scopus)

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 longchain 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.

Original language	English
Pages (from-to)	32433-32442
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	51
DOIs	https://doi.org/10.1073/pnas.2006828117
Publication status	Published - 2020 Dec 22

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS–2020–GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835).

Funding Information:
We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS-2020-GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

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10.1073/pnas.2006828117

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Lee, J. Y., Nam, M., Son, H. Y., Hyun, K., Jang, S. Y., Kim, J. W., Kim, M. W., Jung, Y., Jang, E., Yoon, S. J., Kim, J., Kim, J., Seo, J., Min, J. K., Oh, K. J., Han, B. S., Kim, W. K., Bae, K. H., Song, J., ... Lee, S. C. (2020). Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proceedings of the National Academy of Sciences of the United States of America, 117(51), 32433-32442. https://doi.org/10.1073/pnas.2006828117

@article{b881cf60e0e944a791b1a4a19bd839bb,

title = "Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer",

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 longchain 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.",

author = "Lee, {Ji Yoon} and Miso Nam and Son, {Hye Young} and Kwangbeom Hyun and Jang, {Seo Young} and Kim, {Jong Woo} and Kim, {Min Wook} and Youngae Jung and Eunji Jang and Yoon, {Seon Jin} and Jungeun Kim and Jihye Kim and Jinho Seo and Min, {Jeong Ki} and Oh, {Kyoung Jin} and Han, {Baek Soo} and Kim, {Won Kon} and Bae, {Kwang Hee} and Jaewhan Song and Jaehoon Kim and Huh, {Yong Min} and Hwang, {Geum Sook} and Lee, {Eun Woo} and Lee, {Sang Chul}",

note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS–2020–GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835). Funding Information: We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS-2020-GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835). Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",

year = "2020",

month = dec,

day = "22",

doi = "10.1073/pnas.2006828117",

language = "English",

volume = "117",

pages = "32433--32442",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "51",

}

Lee, JY, Nam, M, Son, HY, Hyun, K, Jang, SY, Kim, JW, Kim, MW, Jung, Y, Jang, E, Yoon, SJ, Kim, J, Kim, J, Seo, J, Min, JK, Oh, KJ, Han, BS, Kim, WK, Bae, KH, Song, J, Kim, J, Huh, YM, Hwang, GS, Lee, EW & Lee, SC 2020, 'Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 51, pp. 32433-32442. https://doi.org/10.1073/pnas.2006828117

TY - JOUR

T1 - Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

AU - Lee, Ji Yoon

AU - Nam, Miso

AU - Son, Hye Young

AU - Hyun, Kwangbeom

AU - Jang, Seo Young

AU - Kim, Jong Woo

AU - Kim, Min Wook

AU - Jung, Youngae

AU - Jang, Eunji

AU - Yoon, Seon Jin

AU - Kim, Jungeun

AU - Kim, Jihye

AU - Seo, Jinho

AU - Min, Jeong Ki

AU - Oh, Kyoung Jin

AU - Han, Baek Soo

AU - Kim, Won Kon

AU - Bae, Kwang Hee

AU - Song, Jaewhan

AU - Kim, Jaehoon

AU - Huh, Yong Min

AU - Hwang, Geum Sook

AU - Lee, Eun Woo

AU - Lee, Sang Chul

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS–2020–GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835). Funding Information: We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS-2020-GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835). Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.

PY - 2020/12/22

Y1 - 2020/12/22

N2 - 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 longchain 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.

AB - 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 longchain 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.

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U2 - 10.1073/pnas.2006828117

DO - 10.1073/pnas.2006828117

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AN - SCOPUS:85098227709

SN - 0027-8424

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EP - 32442

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 51

ER -

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Abstract

Bibliographical note

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