Cysteine depletion induces pancreatic tumor ferroptosis in mice
Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show th...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2020-04, Vol.368 (6486), p.85-89 |
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| creator | Badgley, Michael A Kremer, Daniel M Maurer, H Carlo DelGiorno, Kathleen E Lee, Ho-Joon Purohit, Vinee Sagalovskiy, Irina R Ma, Alice Kapilian, Jonathan Firl, Christina E M Decker, Amanda R Sastra, Steve A Palermo, Carmine F Andrade, Leonardo R Sajjakulnukit, Peter Zhang, Li Tolstyka, Zachary P Hirschhorn, Tal Lamb, Candice Liu, Tong Gu, Wei Seeley, E Scott Stone, Everett Georgiou, George Manor, Uri Iuga, Alina Wahl, Geoffrey M Stockwell, Brent R Lyssiotis, Costas A Olive, Kenneth P |
| description | Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x
is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x
subunit,
, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC. |
| doi_str_mv | 10.1126/science.aaw9872 |
| format | Article |
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is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x
subunit,
, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aaw9872</identifier><identifier>PMID: 32241947</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Adenocarcinoma ; Amino acids ; Animals ; Apoptosis ; Cancer ; Carcinoma, Pancreatic Ductal - metabolism ; Carcinoma, Pancreatic Ductal - pathology ; Cationic Amino Acid Transporter 1 - genetics ; Cell death ; Cell Line, Tumor ; Coenzyme A ; Cystathionine gamma-Lyase - administration & dosage ; Cystathionine gamma-Lyase - pharmacology ; Cysteine ; Cysteine - deficiency ; Cystine ; Cystine - metabolism ; Depletion ; Ferroptosis ; Ferroptosis - drug effects ; Ferroptosis - genetics ; Gene Deletion ; Genetic engineering ; Glutathione ; Humans ; Imports ; Intracellular levels ; Lipids ; Metabolites ; Mice ; Mice, Mutant Strains ; Mortality ; Oxygen ; Pancreatic cancer ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Reactive oxygen species ; Tumors</subject><ispartof>Science (American Association for the Advancement of Science), 2020-04, Vol.368 (6486), p.85-89</ispartof><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-8acc35f00e56e67e849e0f1c716c9952ab41f9e9f661fbd53069254b46c3e5e43</citedby><cites>FETCH-LOGICAL-c487t-8acc35f00e56e67e849e0f1c716c9952ab41f9e9f661fbd53069254b46c3e5e43</cites><orcidid>0000-0002-1480-2368 ; 0000-0001-8093-5540 ; 0000-0003-4195-9819 ; 0000-0002-5749-8394 ; 0000-0002-8823-3073 ; 0000-0002-8556-7481 ; 0000-0001-6224-0550 ; 0000-0001-9319-3531 ; 0000-0002-2745-696X ; 0000-0002-0703-7506 ; 0000-0001-9309-6141 ; 0000-0002-9107-6283 ; 0000-0002-3532-3868 ; 0000-0003-3658-2279 ; 0000-0001-9969-7909 ; 0000-0003-3684-2173 ; 0000-0002-9802-1955 ; 0000-0002-6204-2156 ; 0000-0002-2193-6014 ; 0000-0002-3392-8994 ; 0000-0002-0004-5677 ; 0000-0002-2351-8289 ; 0000-0003-3616-5387</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32241947$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Badgley, Michael A</creatorcontrib><creatorcontrib>Kremer, Daniel M</creatorcontrib><creatorcontrib>Maurer, H Carlo</creatorcontrib><creatorcontrib>DelGiorno, Kathleen E</creatorcontrib><creatorcontrib>Lee, Ho-Joon</creatorcontrib><creatorcontrib>Purohit, Vinee</creatorcontrib><creatorcontrib>Sagalovskiy, Irina R</creatorcontrib><creatorcontrib>Ma, Alice</creatorcontrib><creatorcontrib>Kapilian, Jonathan</creatorcontrib><creatorcontrib>Firl, Christina E M</creatorcontrib><creatorcontrib>Decker, Amanda R</creatorcontrib><creatorcontrib>Sastra, Steve A</creatorcontrib><creatorcontrib>Palermo, Carmine F</creatorcontrib><creatorcontrib>Andrade, Leonardo R</creatorcontrib><creatorcontrib>Sajjakulnukit, Peter</creatorcontrib><creatorcontrib>Zhang, Li</creatorcontrib><creatorcontrib>Tolstyka, Zachary P</creatorcontrib><creatorcontrib>Hirschhorn, Tal</creatorcontrib><creatorcontrib>Lamb, Candice</creatorcontrib><creatorcontrib>Liu, Tong</creatorcontrib><creatorcontrib>Gu, Wei</creatorcontrib><creatorcontrib>Seeley, E Scott</creatorcontrib><creatorcontrib>Stone, Everett</creatorcontrib><creatorcontrib>Georgiou, George</creatorcontrib><creatorcontrib>Manor, Uri</creatorcontrib><creatorcontrib>Iuga, Alina</creatorcontrib><creatorcontrib>Wahl, Geoffrey M</creatorcontrib><creatorcontrib>Stockwell, Brent R</creatorcontrib><creatorcontrib>Lyssiotis, Costas A</creatorcontrib><creatorcontrib>Olive, Kenneth P</creatorcontrib><title>Cysteine depletion induces pancreatic tumor ferroptosis in mice</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x
is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x
subunit,
, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.</description><subject>Adenocarcinoma</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cationic Amino Acid Transporter 1 - genetics</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Coenzyme A</subject><subject>Cystathionine gamma-Lyase - administration & dosage</subject><subject>Cystathionine gamma-Lyase - pharmacology</subject><subject>Cysteine</subject><subject>Cysteine - deficiency</subject><subject>Cystine</subject><subject>Cystine - metabolism</subject><subject>Depletion</subject><subject>Ferroptosis</subject><subject>Ferroptosis - drug effects</subject><subject>Ferroptosis - genetics</subject><subject>Gene Deletion</subject><subject>Genetic engineering</subject><subject>Glutathione</subject><subject>Humans</subject><subject>Imports</subject><subject>Intracellular levels</subject><subject>Lipids</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Mortality</subject><subject>Oxygen</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Reactive oxygen 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depletion induces pancreatic tumor ferroptosis in mice</title><author>Badgley, Michael A ; Kremer, Daniel M ; Maurer, H Carlo ; DelGiorno, Kathleen E ; Lee, Ho-Joon ; Purohit, Vinee ; Sagalovskiy, Irina R ; Ma, Alice ; Kapilian, Jonathan ; Firl, Christina E M ; Decker, Amanda R ; Sastra, Steve A ; Palermo, Carmine F ; Andrade, Leonardo R ; Sajjakulnukit, Peter ; Zhang, Li ; Tolstyka, Zachary P ; Hirschhorn, Tal ; Lamb, Candice ; Liu, Tong ; Gu, Wei ; Seeley, E Scott ; Stone, Everett ; Georgiou, George ; Manor, Uri ; Iuga, Alina ; Wahl, Geoffrey M ; Stockwell, Brent R ; Lyssiotis, Costas A ; Olive, Kenneth P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-8acc35f00e56e67e849e0f1c716c9952ab41f9e9f661fbd53069254b46c3e5e43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenocarcinoma</topic><topic>Amino 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Strains</topic><topic>Mortality</topic><topic>Oxygen</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Reactive oxygen species</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Badgley, Michael A</creatorcontrib><creatorcontrib>Kremer, Daniel M</creatorcontrib><creatorcontrib>Maurer, H Carlo</creatorcontrib><creatorcontrib>DelGiorno, Kathleen E</creatorcontrib><creatorcontrib>Lee, Ho-Joon</creatorcontrib><creatorcontrib>Purohit, Vinee</creatorcontrib><creatorcontrib>Sagalovskiy, Irina R</creatorcontrib><creatorcontrib>Ma, Alice</creatorcontrib><creatorcontrib>Kapilian, Jonathan</creatorcontrib><creatorcontrib>Firl, Christina E M</creatorcontrib><creatorcontrib>Decker, Amanda R</creatorcontrib><creatorcontrib>Sastra, Steve A</creatorcontrib><creatorcontrib>Palermo, Carmine F</creatorcontrib><creatorcontrib>Andrade, Leonardo 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R</au><au>Sajjakulnukit, Peter</au><au>Zhang, Li</au><au>Tolstyka, Zachary P</au><au>Hirschhorn, Tal</au><au>Lamb, Candice</au><au>Liu, Tong</au><au>Gu, Wei</au><au>Seeley, E Scott</au><au>Stone, Everett</au><au>Georgiou, George</au><au>Manor, Uri</au><au>Iuga, Alina</au><au>Wahl, Geoffrey M</au><au>Stockwell, Brent R</au><au>Lyssiotis, Costas A</au><au>Olive, Kenneth P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cysteine depletion induces pancreatic tumor ferroptosis in mice</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2020-04-03</date><risdate>2020</risdate><volume>368</volume><issue>6486</issue><spage>85</spage><epage>89</epage><pages>85-89</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x
is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x
subunit,
, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>32241947</pmid><doi>10.1126/science.aaw9872</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-1480-2368</orcidid><orcidid>https://orcid.org/0000-0001-8093-5540</orcidid><orcidid>https://orcid.org/0000-0003-4195-9819</orcidid><orcidid>https://orcid.org/0000-0002-5749-8394</orcidid><orcidid>https://orcid.org/0000-0002-8823-3073</orcidid><orcidid>https://orcid.org/0000-0002-8556-7481</orcidid><orcidid>https://orcid.org/0000-0001-6224-0550</orcidid><orcidid>https://orcid.org/0000-0001-9319-3531</orcidid><orcidid>https://orcid.org/0000-0002-2745-696X</orcidid><orcidid>https://orcid.org/0000-0002-0703-7506</orcidid><orcidid>https://orcid.org/0000-0001-9309-6141</orcidid><orcidid>https://orcid.org/0000-0002-9107-6283</orcidid><orcidid>https://orcid.org/0000-0002-3532-3868</orcidid><orcidid>https://orcid.org/0000-0003-3658-2279</orcidid><orcidid>https://orcid.org/0000-0001-9969-7909</orcidid><orcidid>https://orcid.org/0000-0003-3684-2173</orcidid><orcidid>https://orcid.org/0000-0002-9802-1955</orcidid><orcidid>https://orcid.org/0000-0002-6204-2156</orcidid><orcidid>https://orcid.org/0000-0002-2193-6014</orcidid><orcidid>https://orcid.org/0000-0002-3392-8994</orcidid><orcidid>https://orcid.org/0000-0002-0004-5677</orcidid><orcidid>https://orcid.org/0000-0002-2351-8289</orcidid><orcidid>https://orcid.org/0000-0003-3616-5387</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2020-04, Vol.368 (6486), p.85-89 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7681911 |
| source | American Association for the Advancement of Science; MEDLINE |
| subjects | Adenocarcinoma Amino acids Animals Apoptosis Cancer Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cationic Amino Acid Transporter 1 - genetics Cell death Cell Line, Tumor Coenzyme A Cystathionine gamma-Lyase - administration & dosage Cystathionine gamma-Lyase - pharmacology Cysteine Cysteine - deficiency Cystine Cystine - metabolism Depletion Ferroptosis Ferroptosis - drug effects Ferroptosis - genetics Gene Deletion Genetic engineering Glutathione Humans Imports Intracellular levels Lipids Metabolites Mice Mice, Mutant Strains Mortality Oxygen Pancreatic cancer Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Reactive oxygen species Tumors |
| title | Cysteine depletion induces pancreatic tumor ferroptosis in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T05%3A19%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cysteine%20depletion%20induces%20pancreatic%20tumor%20ferroptosis%20in%20mice&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Badgley,%20Michael%20A&rft.date=2020-04-03&rft.volume=368&rft.issue=6486&rft.spage=85&rft.epage=89&rft.pages=85-89&rft.issn=0036-8075&rft.eissn=1095-9203&rft_id=info:doi/10.1126/science.aaw9872&rft_dat=%3Cproquest_pubme%3E2385808150%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2385808150&rft_id=info:pmid/32241947&rfr_iscdi=true |