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.

Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue

“…All procedures were performed in accordance with the Institutional Animal Care and Use Committees at Keimyung University School of Medicine, Daegu, South Korea (KM-2015-32R3). Four-week-old male IDH2KO mice 8 and WT littermates with the same genetic background (C57BL/6J) were used for this study. No randomization of the mice was used.…”

Increased susceptibility of IDH2-deficient mice to dextran sodium sulfate-induced colitis

“…3F) were significantly higher in IDH2 -/- mice compared to IDH2 +/+ mice. Lipid peroxidation was measured for the HNE protein adduct analysis using an anti-HNE antibody, and the levels of oxidative protein damage were measured by determining the number of derivatized carbonyl groups on oxidized proteins by immunoblotting [28]. Oxidative DNA damage was evaluated by measuring the level of 8-OH-dG adducts in DNA using an 8-OH-dG antibody [42].…”

“…Experiments were performed using 8-week-old male C57BL/6 mice with different genotypes, including wild-type IDH2 +/+ and knockout IDH2 -/- mice, generated by breeding and identified by PCR genotyping, as previously described [28]. The mice were housed in microisolator rodent cages at 22 °C with a 12 h light/dark cycle and allowed free access to water and standard mouse chow.…”

IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice

“…Animals used in this study were idh2 À / À germ-line knockout (IDH2 KO) male mice and their congenic background strain (C57BL/6 J) male mice, which served as the WT (idh2 þ / þ ) control [17]. The animals were housed at 22 1C with a 12-h light/dark cycle and had free access to water and standard chow.…”