Suppression of tumorigenesis in mitochondrial NADP(+)-dependent isocitrate dehydrogenase knock-out mice.

Abstract

The tumor host microenvironment is increasingly viewed as an important contributor to tumor growth and suppression. Cellular oxidative stress resulting from high levels of reactive oxygen species (ROS) contributes to various processes involved in the development and progress of malignant tumors including carcinogenesis, aberrant growth, metastasis, and angiogenesis. In this regard, the stroma induces oxidative stress in adjacent tumor cells, and this in turn causes several changes in tumor cells including modulation of the redox status, inhibition of cell proliferation, and induction of apoptotic or necrotic cell death. Because the levels of ROS are determined by a balance between ROS generation and ROS detoxification, disruption of this system will result in increased or decreased ROS level. Recently, we demonstrated that the control of mitochondrial redox balance and cellular defense against oxidative damage is one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) that supplies NADPH for antioxidant systems. To explore the interactions between tumor cells and the host, we evaluated tumorigenesis between IDH2-deficient (knock-out) and wild-type mice in which B16F10 melanoma cells had been implanted. Suppression of B16F10 cell tumorigenesis was reproducibly observed in the IDH2-deficient mice along with significant elevation of oxidative stress in both the tumor and the stroma. In addition, the expression of angiogenesis markers was significantly down-regulated in both the tumor and the stroma of the IDH2-deficient mice. These results support the hypothesis that redox status-associated changes in the host environment of tumor-bearing mice may contribute to cancer progression.

• Authors: Seontae Kim, Sung Youl Kim, Hyeong Jun Ku, Yong Hyun Jeon, Ho Won Lee, Jaetae Lee, Taeg Kyu Kwon, Kwon Moo Park, Jeen-Woo Park
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1842 Issue 2 Pg. 135-43 (Feb 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24240089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Glucose Transporter Type 1
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mitochondrial Proteins
• Reactive Oxygen Species
• Slc2a1 protein, mouse
• Vascular Endothelial Growth Factor A
• Hydrogen Peroxide
• Isocitrate Dehydrogenase
• isocitrate dehydrogenase (NADP+)

Topics

• Animals
• Carcinogenesis (genetics, metabolism)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Glucose Transporter Type 1 (genetics, metabolism)
• Hydrogen Peroxide (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Immunoblotting
• Isocitrate Dehydrogenase (genetics, metabolism)
• Male
• Melanoma, Experimental (genetics, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Proteins (genetics, metabolism)
• Oxidative Stress
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Burden (genetics)
• Vascular Endothelial Growth Factor A (genetics, metabolism)