xCT deficiency accelerates chemically induced tumorigenesis.

Abstract

During the course of inflammation and its resolution, macrophages are exposed to various cytotoxic materials, including reactive oxygen species. Thus, macrophages require a protective machinery against oxidative stress to survive at the inflammatory site. Here, we showed that xCT, a component of transport system x(c)(-), was significantly up-regulated in activated infiltrating cells, including macrophages and neutrophils at the inflammatory site. System x(c)(-) mediates the uptake of extracellular L-cystine and is consequently responsible for maintenance of intracellular glutathione levels. We established a loss-of-function mouse mutant line of xCT by N-ethyl-N-nitrosourea mutagenesis. Macrophages from xCT(mu/mu) mice showed cell death in association with the excessive release of high mobility group box chromosomal protein 1 upon stimulation with LPS, suggesting that xCT deficiency causes unremitting inflammation because of the impaired survival of activated macrophages at the inflammatory site. Subcutaneous injection of 3-methylcholanthrene (3-MCA) induced the generation of fibrosarcoma in association with inflammation. When 3-MCA was injected s.c. into mice, xCT mRNA was up-regulated in situ. In xCT(mu/mu) mice, inflammatory cytokines (such as IL-1beta and TNFalpha) were overexpressed, and the generation of 3-MCA-induced fibrosarcoma was accelerated. These results clearly indicate that the defect of the protective system against oxidative stress impaired survival of activated macrophages and subsequently enhanced tumorigenecity.

• Authors: Ami Nabeyama, Ai Kurita, Kenichi Asano, Yasunobu Miyake, Takuwa Yasuda, Ikuo Miura, Gen Nishitai, Satoko Arakawa, Shigeomi Shimizu, Shigeharu Wakana, Hisahiro Yoshida, Masato Tanaka
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 14 Pg. 6436-41 (Apr 06 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20308543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport System y+
• Interleukin-1beta
• Slc7a11 protein, mouse
• Tumor Necrosis Factor-alpha
• Methylcholanthrene

Topics

• Amino Acid Transport System y+ (deficiency, immunology, metabolism)
• Animals
• Cell Death
• Cell Transformation, Neoplastic (chemically induced, genetics, immunology, metabolism)
• Fibrosarcoma (chemically induced, immunology, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Interleukin-1beta (immunology)
• Methylcholanthrene
• Mice
• Mice, Knockout
• Tumor Necrosis Factor-alpha (immunology)
• Up-Regulation