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: Keiichiro Hiramoto, Hironori Satoh, Takafumi Suzuki, Takashi Moriguchi, Jingbo Pi, Tooru Shimosegawa, Masayuki Yamamoto
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 7 Issue 8 Pg. 835-44 (Aug 2014) ISSN: 1940-6215 [Electronic] United States
• PMID: 24866179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antioxidants
• Imidazoles
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• RNA, Transfer, Amino Acid-Specific
• Reactive Oxygen Species
• tRNA, selenocysteine-
• imidazole

Topics

• Animals
• Antioxidants (metabolism)
• Cell Line, Tumor
• Cell Lineage
• Gene Deletion
• Imidazoles (chemistry)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells (cytology)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neoplasms (metabolism, pathology)
• Oxidative Stress
• RNA, Transfer, Amino Acid-Specific (genetics, metabolism)
• Reactive Oxygen Species (metabolism)