The L-Arginine Dependent Effector Mechanism Is Induced in Murine Adenocarcinoma Cells by Culture Supernatant From Cytotoxic Activated Macrophages

Amber, Ina J.; Hibbs, John B.; Taintor, Read R.; Vavrin, Zdenek

doi:10.1002/jlb.43.2.187

Cited by 61 publications

(24 citation statements)

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“…Mammary adenocarcinoma EMT6 cells are a widely used model to study different aspects of growth control in cancer (21)(22)(23)(24)(25). A broad variety of chemical compounds (23), growth factor inhibitors, and other biomolecules, including cytokines either alone or in combination with endocrine modulation (22), have been studied using in vitro and in vivo settings in this model.…”

Section: Il-22-mediated Tumor Growth Reduction Correlates With Inhibimentioning

confidence: 99%

IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase

Weber

Gaertner

Erl

et al. 2006

The Journal of Immunology

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IL-22 is a recently discovered cytokine of the IL-10 family that binds to a class II cytokine receptor composed of IL-22R1 and IL-10R2c and influences a variety of immune reactions. As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo. In this study, we report that murine breast cancer cells express functional IL-22R as indicated by RT-PCR studies, immunoblotting, and STAT3 activation assays. Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation. Furthermore, IL-22 induced a cell cycle arrest of EMT6 cells in the G2-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by ∼50% as measured by [3H]thymidine incorporation. IL-22 treatment of EMT6 tumor-bearing mice lead to a decreased tumor size and a reduced tumor cell proliferation in vivo, as determined by 3′-deoxy-3′-fluorothymidine-positron emission tomography scans. Interestingly, IL-22 did not induce apoptosis, as determined in annexin V binding assay and caspase-3 activation assay and had no effect on angiogenesis in vivo. In conclusion, our results indicate that IL-22 reduced tumor growth by inhibiting signaling pathways such as ERK1/2 and AKT phosphorylation that promote tumor cell proliferation in EMT6 cells. Therefore, IL-22 may play a role in the control of tumor growth and tumor progression.

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Section: Il-22-mediated Tumor Growth Reduction Correlates With Inhibimentioning

confidence: 99%

IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase

Weber

Gaertner

Erl

et al. 2006

The Journal of Immunology

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“…The inhibition of NO production delayed the rejection of a highly antigenic murine skin tumor (23), and tumor-mediated suppression of macrophage iNOS expression and deletion of the host iNOS gene were both correlated with reduced tumor rejection (24,25). However, it has been suggested that induction of NO synthesis in the tumors cells themselves could also contribute to tumor rejection (10,23,26). The cytokines that induce NO synthesis by tumor-infiltrating macrophages can also induce NO synthesis in tumor cells, resulting in their growth arrest and apoptosis (10,26).…”

Section: Introductionmentioning

confidence: 99%

“…However, it has been suggested that induction of NO synthesis in the tumors cells themselves could also contribute to tumor rejection (10,23,26). The cytokines that induce NO synthesis by tumor-infiltrating macrophages can also induce NO synthesis in tumor cells, resulting in their growth arrest and apoptosis (10,26).…”

Section: Introductionmentioning

confidence: 99%

Tumor Cell-Derived Nitric Oxide Is Involved in the Immune-Rejection of an Immunogenic Murine Lymphoma

Dyke

Moore

et al. 2004

Cancer Research

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The roles played by host-derived nitric oxide (NO) in the growth and subsequent immune rejection of a immunogenic murine lymphoma were investigated by growing the tumor in mice in which the gene for either inducible NO synthase (iNOS) or endothelial NOS (eNOS) had been ablated. This showed that NO from tumor-infiltrating host cells had no significant effect on either tumor growth or immune rejection, although measurements of tumor nitrite levels and protein nitration showed that there had been significant NO production in the rejected tumors, in both the eNOS and iNOS knockout mice. Inhibition of both tumor and host NOS activities, with an iNOS-selective inhibitor (1400W), a nonselective NOS inhibitor [N-nitro-L-arginine methyl ester (L-NAME)], or scavenging NO with a ruthenium-based scavenger, significantly delayed tumor rejection, while having no appreciable effect on tumor growth. Incubation of tumor cells with medium taken from cultured splenocytes, that had been isolated from immunized animals and activated by incubating them with irradiated tumor cells, resulted in an increase in tumor cell NOS activity and an increase in tumor cell apoptosis, which could be inhibited using L-NAME. We propose that, during the immune rejection of this tumor model, there is induction of tumor NOS activity by cytokines secreted by activated lymphocytes within the tumor and that this results in increased levels of tumor NO that induce tumor cell apoptosis and facilitate immune rejection of the tumor.

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“…Nitric oxide (NO), a potentially toxic gas with free radical properties, is generated from L-arginine by constitutive or inducible NO synthase (NOS). 4) It has been reported that different isoforms of NOS are expressed in not only human tumor cell lines, [5][6][7] but also solid tumor tissues. [8][9][10] We recently reported that the total NOS activity in lung adenocarcinoma samples was significantly higher than that in other types of lung cancers and normal lung samples.…”

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confidence: 99%

Significant Correlation of Nitric Oxide Synthase Activity and p53 Gene Mutation in Stage I Lung Adenocarcinoma

Fujimoto

Sasaki

Matsumoto

et al. 1998

Japanese Journal of Cancer Research

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Nitric oxide (NO) and its derivatives can directly cause DNA damage and mutation in vitro and may play a role in the multistage carcinogenic process. It has been reported that NO induces mutation in the p53 tumor suppressor gene; we therefore analyzed the relationship between NO synthase 9 activity and p53 gene status in early-stage lung adenocarcinoma. Surgical samples were classified into two categories: 14 lung adenocarcinomas with high NOS activity (> > > >25 pmol/ min/g tissue, category A), and 16 with low NOS activity (< < < <25 pmol/min/g tissue, category B). A yeast functional assay for p53 mutations disclosed a red colony that corresponded to a mutation in the p53 gene in 8 cases (57.1%) in category A and 3 cases (18.8%) in category B, the frequency being significantly higher in the former (P< < < <0.05). A p53 DNA sequence analysis revealed that 5 of the 8 p53 mutation-positive samples in category A had a G:C-to-T:A transversion, which is reported to be a major target of NO. The mechanism of carcinogenesis of adenocarcinoma is not fully understood, but these results suggest that an excess of endogenously formed NO may induce a p53 gene mutation containing mainly G:C-to-T:A transversion in the early stage of lung adenocarcinoma. Our results suggest that NO has potential mutagenic and carcinogenic activity, and may play important roles in human lung adenocarcinoma.

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The L-Arginine Dependent Effector Mechanism Is Induced in Murine Adenocarcinoma Cells by Culture Supernatant From Cytotoxic Activated Macrophages

Cited by 61 publications

References 0 publications

IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase

IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase

Tumor Cell-Derived Nitric Oxide Is Involved in the Immune-Rejection of an Immunogenic Murine Lymphoma

Significant Correlation of Nitric Oxide Synthase Activity and p53 Gene Mutation in Stage I Lung Adenocarcinoma

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