Ferroptosis resistance determines high susceptibility of murine <i>A/J</i> strain to iron‐induced renal carcinogenesis

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  • Zhen Cheng
    Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
  • Shinya Akatsuka
    Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
  • Guang Hua Li
    Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
  • Kiyoshi Mori
    Graduate School of Public Health Shizuoka Graduate University of Public Health Shizuoka Japan
  • Takashi Takahashi
    Aichi Cancer Center Research Institute Nagoya Japan
  • Shinya Toyokuni
    Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan

書誌事項

公開日
2021-11-23
資源種別
journal article
権利情報
  • http://creativecommons.org/licenses/by-nc-nd/4.0/
DOI
  • 10.1111/cas.15175
公開者
Wiley

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説明

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>C57BL/6J</jats:italic> strain mice, we investigated <jats:italic>A/J</jats:italic> strain mice here, which demonstrated significantly higher susceptibility to Fe‐NTA‐induced renal carcinogenesis. Homozygous deletion of the <jats:italic>Cdkn2a/2b</jats:italic> tumor suppressor locus was detected for the first time in <jats:italic>A/J</jats:italic> 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 <jats:italic>A/J</jats:italic> and <jats:italic>C57BL/6J</jats:italic> strains after Fe‐NTA treatment. After 3‐week Fe‐NTA treatment, <jats:italic>A/J</jats:italic> mice maintained higher levels of expression of glutathione peroxidase 4 and <jats:italic>x</jats:italic>CT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, <jats:italic>A/J</jats:italic> mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than <jats:italic>C57BL/6</jats:italic> mice. After a single Fe‐NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in <jats:italic>C57BL/6J</jats:italic> 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 <jats:italic>A/J</jats:italic> strain.</jats:p>

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