Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis
Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe‐NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeate...
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| Veröffentlicht in: | Cancer science 2022-01, Vol.113 (1), p.65-78 |
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| creator | Cheng, Zhen Akatsuka, Shinya Li, Guang Hua Mori, Kiyoshi Takahashi, Takashi Toyokuni, Shinya |
| description | Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe‐NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe‐NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter‐strain difference in the susceptibility to Fe‐NTA‐induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe‐NTA‐induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe‐NTA treatment. After 3‐week Fe‐NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe‐NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin‐2. Lipocalin‐2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe‐NTA‐induced RCC in A/J strain.
Cancer susceptibility is an important issue when considering cancer prevention. In this paper, we used an iron‐mediated oxidative stress‐induced renal carcinogenesis model in mice and found that ferroptosis resistance is an important factor determining cancer susceptibility. |
| doi_str_mv | 10.1111/cas.15175 |
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Cancer susceptibility is an important issue when considering cancer prevention. In this paper, we used an iron‐mediated oxidative stress‐induced renal carcinogenesis model in mice and found that ferroptosis resistance is an important factor determining cancer susceptibility.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.15175</identifier><identifier>PMID: 34699654</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>animal models ; Animals ; Antibodies ; Carcinogenesis ; Carcinoma, Renal Cell - chemically induced ; Carcinoma, Renal Cell - genetics ; Carcinoma, Renal Cell - pathology ; Cationic Amino Acid Transporter 1 - genetics ; Cyclin-Dependent Kinase Inhibitor p15 - genetics ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Drug dosages ; Experiments ; Ferric Compounds - adverse effects ; Ferritin ; Ferritins - genetics ; Ferroptosis ; Free radicals ; Gene deletion ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Glutathione peroxidase ; Homozygote ; Hydroxyl radicals ; Injection ; Injections, Intraperitoneal ; Iron ; Kidney Neoplasms - chemically induced ; Kidney Neoplasms - genetics ; Kidney Neoplasms - pathology ; Kidneys ; Laboratory animals ; Lipid Peroxidation ; Lipocalin ; Lipocalin-2 - genetics ; lipocalins ; Male ; Medical research ; Mice ; Molecular modelling ; Mutation ; Neoplasms, Experimental ; Nitrilotriacetic Acid - adverse effects ; Nitrilotriacetic Acid - analogs & derivatives ; Original ; Oxidative Stress ; Proteins ; Proximal tubules ; Receptors, Transferrin - genetics ; Renal cell carcinoma ; Sequence Deletion ; Species Specificity ; Susceptibility ; Transferrins ; Tumor suppressor genes ; Tumors ; Up-Regulation</subject><ispartof>Cancer science, 2022-01, Vol.113 (1), p.65-78</ispartof><rights>2021 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2022. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5335-a90bb7757d0cb4bddf482a6d95f00006f5996a09ca923a20874eaef93f28b81d3</citedby><cites>FETCH-LOGICAL-c5335-a90bb7757d0cb4bddf482a6d95f00006f5996a09ca923a20874eaef93f28b81d3</cites><orcidid>0000-0002-5757-1109 ; 0000-0003-0615-7001</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748236/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748236/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,1412,11543,27905,27906,45555,45556,46033,46457,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34699654$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheng, Zhen</creatorcontrib><creatorcontrib>Akatsuka, Shinya</creatorcontrib><creatorcontrib>Li, Guang Hua</creatorcontrib><creatorcontrib>Mori, Kiyoshi</creatorcontrib><creatorcontrib>Takahashi, Takashi</creatorcontrib><creatorcontrib>Toyokuni, Shinya</creatorcontrib><title>Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe‐NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe‐NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter‐strain difference in the susceptibility to Fe‐NTA‐induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe‐NTA‐induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe‐NTA treatment. After 3‐week Fe‐NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe‐NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin‐2. Lipocalin‐2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe‐NTA‐induced RCC in A/J strain.
Cancer susceptibility is an important issue when considering cancer prevention. In this paper, we used an iron‐mediated oxidative stress‐induced renal carcinogenesis model in mice and found that ferroptosis resistance is an important factor determining cancer susceptibility.</description><subject>animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Carcinogenesis</subject><subject>Carcinoma, Renal Cell - chemically induced</subject><subject>Carcinoma, Renal Cell - genetics</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>Cationic Amino Acid Transporter 1 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p15 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Drug dosages</subject><subject>Experiments</subject><subject>Ferric Compounds - adverse effects</subject><subject>Ferritin</subject><subject>Ferritins - genetics</subject><subject>Ferroptosis</subject><subject>Free radicals</subject><subject>Gene deletion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Glutathione peroxidase</subject><subject>Homozygote</subject><subject>Hydroxyl radicals</subject><subject>Injection</subject><subject>Injections, Intraperitoneal</subject><subject>Iron</subject><subject>Kidney Neoplasms - chemically induced</subject><subject>Kidney Neoplasms - genetics</subject><subject>Kidney Neoplasms - pathology</subject><subject>Kidneys</subject><subject>Laboratory animals</subject><subject>Lipid Peroxidation</subject><subject>Lipocalin</subject><subject>Lipocalin-2 - genetics</subject><subject>lipocalins</subject><subject>Male</subject><subject>Medical research</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>Mutation</subject><subject>Neoplasms, Experimental</subject><subject>Nitrilotriacetic Acid - adverse effects</subject><subject>Nitrilotriacetic Acid - analogs & derivatives</subject><subject>Original</subject><subject>Oxidative Stress</subject><subject>Proteins</subject><subject>Proximal tubules</subject><subject>Receptors, Transferrin - genetics</subject><subject>Renal cell carcinoma</subject><subject>Sequence Deletion</subject><subject>Species Specificity</subject><subject>Susceptibility</subject><subject>Transferrins</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><subject>Up-Regulation</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUtOwzAQhi0E4r3gAsgSKxahTpzE8QapqigPVWIBrC3HnrRGqV3sBNQdR-CMnATTAoIFs7AtzafPM_oROkrJWRproGQ4S4uUFRtoN6U5Txgh5ebqzRJOaLaD9kJ4JISWOc-30Q7NS87LIt9FT2Pw3i06F0zAHuLZSasAa-jAz42FgGdmOsOhDwoWnalNa7oldg2e9z628XBwg0PnpbG4c9h4Z99f34zVvQIdhVa2WEmvjHVTsJ_-A7TVyDbA4de9jx7GF_ejq2Rye3k9Gk4SVVBaJJKTumasYJqoOq-1bvIqk6XmRUNilU0RN5CEK8kzKjNSsRwkNJw2WVVXqab76HztXfT1HLQCG6dsxcKbufRL4aQRfzvWzMTUPYtoqjJaRsHJl8C7px5CJx5d7-NCQWRlWlHGOWWROl1TyrsQPDQ_P6REfKYjYjpilU5kj3-P9EN-xxGBwRp4MS0s_zeJ0fBurfwAFaqdow</recordid><startdate>202201</startdate><enddate>202201</enddate><creator>Cheng, Zhen</creator><creator>Akatsuka, Shinya</creator><creator>Li, Guang Hua</creator><creator>Mori, Kiyoshi</creator><creator>Takahashi, Takashi</creator><creator>Toyokuni, Shinya</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5757-1109</orcidid><orcidid>https://orcid.org/0000-0003-0615-7001</orcidid></search><sort><creationdate>202201</creationdate><title>Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis</title><author>Cheng, Zhen ; Akatsuka, Shinya ; Li, Guang Hua ; Mori, Kiyoshi ; Takahashi, Takashi ; Toyokuni, Shinya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5335-a90bb7757d0cb4bddf482a6d95f00006f5996a09ca923a20874eaef93f28b81d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>animal models</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Carcinogenesis</topic><topic>Carcinoma, Renal Cell - chemically induced</topic><topic>Carcinoma, Renal Cell - genetics</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>Cationic Amino Acid Transporter 1 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p15 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - genetics</topic><topic>Drug dosages</topic><topic>Experiments</topic><topic>Ferric Compounds - adverse effects</topic><topic>Ferritin</topic><topic>Ferritins - genetics</topic><topic>Ferroptosis</topic><topic>Free radicals</topic><topic>Gene deletion</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Regulatory Networks</topic><topic>Glutathione peroxidase</topic><topic>Homozygote</topic><topic>Hydroxyl radicals</topic><topic>Injection</topic><topic>Injections, Intraperitoneal</topic><topic>Iron</topic><topic>Kidney Neoplasms - chemically induced</topic><topic>Kidney Neoplasms - genetics</topic><topic>Kidney Neoplasms - pathology</topic><topic>Kidneys</topic><topic>Laboratory animals</topic><topic>Lipid Peroxidation</topic><topic>Lipocalin</topic><topic>Lipocalin-2 - genetics</topic><topic>lipocalins</topic><topic>Male</topic><topic>Medical research</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>Mutation</topic><topic>Neoplasms, Experimental</topic><topic>Nitrilotriacetic Acid - adverse effects</topic><topic>Nitrilotriacetic Acid - analogs & derivatives</topic><topic>Original</topic><topic>Oxidative Stress</topic><topic>Proteins</topic><topic>Proximal tubules</topic><topic>Receptors, Transferrin - genetics</topic><topic>Renal cell carcinoma</topic><topic>Sequence Deletion</topic><topic>Species Specificity</topic><topic>Susceptibility</topic><topic>Transferrins</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheng, Zhen</creatorcontrib><creatorcontrib>Akatsuka, Shinya</creatorcontrib><creatorcontrib>Li, Guang Hua</creatorcontrib><creatorcontrib>Mori, Kiyoshi</creatorcontrib><creatorcontrib>Takahashi, Takashi</creatorcontrib><creatorcontrib>Toyokuni, Shinya</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheng, Zhen</au><au>Akatsuka, Shinya</au><au>Li, Guang Hua</au><au>Mori, Kiyoshi</au><au>Takahashi, Takashi</au><au>Toyokuni, Shinya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2022-01</date><risdate>2022</risdate><volume>113</volume><issue>1</issue><spage>65</spage><epage>78</epage><pages>65-78</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe‐NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe‐NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter‐strain difference in the susceptibility to Fe‐NTA‐induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe‐NTA‐induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe‐NTA treatment. After 3‐week Fe‐NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe‐NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin‐2. Lipocalin‐2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe‐NTA‐induced RCC in A/J strain.
Cancer susceptibility is an important issue when considering cancer prevention. In this paper, we used an iron‐mediated oxidative stress‐induced renal carcinogenesis model in mice and found that ferroptosis resistance is an important factor determining cancer susceptibility.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>34699654</pmid><doi>10.1111/cas.15175</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-5757-1109</orcidid><orcidid>https://orcid.org/0000-0003-0615-7001</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | animal models Animals Antibodies Carcinogenesis Carcinoma, Renal Cell - chemically induced Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - pathology Cationic Amino Acid Transporter 1 - genetics Cyclin-Dependent Kinase Inhibitor p15 - genetics Cyclin-Dependent Kinase Inhibitor p16 - genetics Drug dosages Experiments Ferric Compounds - adverse effects Ferritin Ferritins - genetics Ferroptosis Free radicals Gene deletion Gene expression Gene Expression Regulation, Neoplastic Gene Regulatory Networks Glutathione peroxidase Homozygote Hydroxyl radicals Injection Injections, Intraperitoneal Iron Kidney Neoplasms - chemically induced Kidney Neoplasms - genetics Kidney Neoplasms - pathology Kidneys Laboratory animals Lipid Peroxidation Lipocalin Lipocalin-2 - genetics lipocalins Male Medical research Mice Molecular modelling Mutation Neoplasms, Experimental Nitrilotriacetic Acid - adverse effects Nitrilotriacetic Acid - analogs & derivatives Original Oxidative Stress Proteins Proximal tubules Receptors, Transferrin - genetics Renal cell carcinoma Sequence Deletion Species Specificity Susceptibility Transferrins Tumor suppressor genes Tumors Up-Regulation |
| title | Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis |
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