Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis

Grimm, Elizabeth A.; Ellerhorst, Julie A.; Tang, Chi; Ekmekçioğlu, Sühendan

doi:10.1016/j.niox.2008.04.009

Cited by 70 publications

(69 citation statements)

References 8 publications

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“…Elevated tumor NOS2 predicts poor survival in breast and other types of cancer (4,5,21,22). We used murine tumor xenographs and cell culture conditions that mimic an aggressive tumor microenvironment including inflammation (cytokines), nutrient deprivation (SW), and hypoxia to examine pathways leading to tumor NOS2 expression and downstream targets of NOS2-derived NO that predict aggressive tumor phenotypes (4).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, these proinflammatory mediators directly correlate with inducible nitric oxide synthase (NOS2), which is an emerging biomarker of aggressive tumors that predicts poor survival in patients with elevated tumor NOS2 expression (4)(5)(6)(7)(8). These and other clinical studies warrant an improved mechanistic understanding of intratumoral NOS2 regulation and endogenous NO production, which may be therapeutically beneficial.…”

mentioning

confidence: 99%

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Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Heinecke¹,

Ridnour²,

Cheng³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

151

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Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER − and ER + breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.I nflammation is a major component of the tumor microenvironment and a driving force in cancer initiation, promotion, and progression (1-3). Epithelial cancers express markers of inflammation that promote disease progression and drug resistance through evasion of cell death pathways and increased tumor metastasis. Rapid cancer growth leads to tumor hypoxia and nutrient deprivation, which promotes chronic inflammatory feed-forward signaling and selection of resistant tumors that are clinically challenging and sometimes untreatable.Several proinflammatory proteins such as COX2, NF-κB, IL-6, IL-8, S100 calcium binding protein A8 (S100A8), and VEGF are markers of chronic inflammation in the tumor microenvironment. In addition, these proinflammatory mediators directly correlate with inducible nitric oxide synthase (NOS2), which is an emerging biomarker of aggressive tumors that predicts poor survival in patients with elevated tumor NOS2 expression (4-8). These and other clinical studies warrant an improved mechanistic understanding of intratumoral NOS2 regulation and endogenous NO production, which may be therapeutically beneficial.Toward this end, our laboratory and others have used NO donors to study NO signaling in cancer. However, intratumoral NOS2 induction by components of the tumor microenv...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Heinecke¹,

Ridnour²,

Cheng³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

151

View full text Add to dashboard Cite

show abstract

“…Our results provide insight into the pharmacology and anticancer activities of VP-16 in tumors that may ultimately contribute to increased resistance and treatment failure. VP-16 is currently used for the treatment of a variety of cancers (e.g., lung, melanoma, and breast) that are known to express iNOS (Chen et al, 2008;Grimm et al, 2008). It is tempting to suggest that the use of VP-16 and related anticancer drugs capable of reacting with × NO/ × NO 2 may be ill-advised for patients harboring cancers with intensive iNOS activity.…”

Section: Discussionmentioning

confidence: 99%

Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells

Sinha

Kumar

Bhattacharjee

et al. 2013

J Pharmacol Exp Ther

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“…[32][33][34][35] Further credence for the observed correlation between iNOS and metastatic disease can be gathered from observations that iNOS and NO directly support growth of cutaneous melanomas. 36 Within our patient cohort with metastatic disease, we observed a trend of iNOS expression in the hepatic filae being accompanied by a high frequency of iNOS positive cells in the primary UM tissue (5/8). Both expression of iNOS in the liver metastasis and high frequency of iNOS in the primary UM in separate analyses predicted shortened survival.…”

Section: Early Detection and Diagnosismentioning

confidence: 59%

Expression and prognostic significance of iNOS in uveal melanoma

Johansson

Mougiakakos

Trocmé

et al. 2010

Intl Journal of Cancer

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Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin-embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p 5 0.04; hazard ratio (HR) 5 2.3) predict disease-specific survival (DSS) as assessed by Kaplan-Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p 5 0.02) predicted a shortened survival as assessed by Kaplan-Meier analysis. However, iNOS did not appear to be a significant (p 5 0.16; HR 5 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.Uveal melanoma (UM) is the most common primary intraocular tumor in adults with an annual incidence of approximately seven cases per million.1 Tumors arise from neural crest-derived melanocytes of the uveal tract including the iris, ciliary body, and choroid of the eye. Even with its low frequency, UM accounts for 13% of all deaths from melanoma. The most common age at diagnosis is 50-60 years. Notwithstanding improvements in the diagnosis and treatment of the primary tumor, the 5-year mortality rate of UM patients has not significantly changed since 1973, and metastasis occurs in 50% of UM patients. 2 The primary target organ for metastasis is the liver, which is involved in up to 87% of the patients with metastatic disease. [3][4][5] Metastases are uniformly fatal despite systemic therapy. 5-7Nitric oxide (NO) produced during the conversion of L-arginine to L-citrulline by NO synthase (NOS) is an important bioactive agent and signaling molecule. Nitric oxide is essential for many physiological functions including vasorelaxation, neurotransmission, and cytotoxicity. The production of NO from L-arginine was first identified in endothelial cells and macrophages. 8,9 It was subsequently demonstrated that inflammatory stimuli induced the expression of a specific isoform of NO synthase (iNOS) in myeloid cells and other cell types.10 There are multiple roles for iNOS in different disease processes.11 A majority of human and experimental tumors are stimulated by NO, which contributes to tumor growth and metastasis by promotin...

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Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis

Cited by 70 publications

References 8 publications

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells

Expression and prognostic significance of iNOS in uveal melanoma

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