title: Myeloid lineage-specific deletion of antioxidant system enhances tumor metastasis.
abstract: Oxidative stress accelerates the pathogenesis of a number of chronic diseases including cancer growth and its metastasis. Transcription factor NF-E2-related factor-2 (Nrf2), which regulates the cellular defense system against oxidative stress, elicits essential protection against chemical-induced carcinogenic insults. We recently demonstrate that the systemic deletion of Nrf2 leads to an increased susceptibility to cancer metastasis, which is associated with aberrant reactive oxygen species (ROS) accumulation in myeloid-derived suppressor cells (MDSC). However, it remains elusive whether cellular antioxidant defense system in the myeloid lineage cells plays indispensable roles for metastatic cancer progression. We herein found that myeloid lineage-specific Nrf2-deficient mice exhibited an increased susceptibility to pulmonary metastasis of the mouse Lewis lung carcinoma cells, and ROS level was more highly elevated in MDSCs of cancer-bearing Nrf2-deficient mice. Similarly, myeloid lineage-specific deletion of selenocysteine-tRNA gene (Trsp), which is essential for synthesis of antioxidant selenoenzymes, resulted in increased number of metastatic nodules along with ROS accumulation in MDSCs of cancer-bearing mice. These results thus indicate that the antioxidant systems directed by Nrf2 and selenoenzymes contribute to the clearance of ROS in MDSCs, efficiently preventing cancer cell metastasis. Consistent with this notion, a synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im), a potent Nrf2 inducer, attenuated the ROS production in MDSCs, and thereafter reduced metastatic nodules. Taken together, this study provides compelling lines of evidence that Nrf2 inducer retains therapeutic efficacy against cancer cell metastasis.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine; Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan; and.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Hiramoto
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine;
authors.forename: Hironori
authors.initials: H
authors.lastname: Satoh
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine; masiyamamoto@med.tohoku.ac.jp taka23@med.tohoku.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine;
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: School of Public Health, China Medical University, Shenyang, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.affiliation: Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan; and.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine; masiyamamoto@med.tohoku.ac.jp taka23@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D017353:Gene Deletion; D007093:Imidazoles / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D012345:RNA, Transfer, Amino Acid-Specific / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012345:RNA, Transfer, Amino Acid-Specific; D017382:Reactive Oxygen Species; C036928:tRNA, selenocysteine-; C029899:imidazole