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Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis
- Source :
- Cancer Science
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
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.<br />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.
- Subjects :
- Male
Nitrilotriacetic Acid
Cancer Research
Carcinogenesis
SLC7A11
GPX4
medicine.disease_cause
Ferric Compounds
Lipid peroxidation
Mice
chemistry.chemical_compound
iron
Gene Regulatory Networks
Sequence Deletion
Kidney
biology
Homozygote
General Medicine
animal models
Kidney Neoplasms
Up-Regulation
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Oncology
Original Article
lipocalins
Injections, Intraperitoneal
renal cell carcinoma
Transferrin receptor
Lipocalin-2
Species Specificity
Receptors, Transferrin
medicine
Animals
Ferroptosis
Carcinoma, Renal Cell
Cell damage
Cyclin-Dependent Kinase Inhibitor p16
Cationic Amino Acid Transporter 1
Cyclin-Dependent Kinase Inhibitor p15
Original Articles
Neoplasms, Experimental
medicine.disease
Molecular biology
Ferritin
Oxidative Stress
chemistry
Ferritins
biology.protein
Lipid Peroxidation
Subjects
Details
- ISSN :
- 13497006 and 13479032
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Cancer Science
- Accession number :
- edsair.doi.dedup.....97dfa42e4379ae6fb7a566239097c5fd