Xanthine oxidoreductase activity in human liver disease

Stirpe, Fiorenzo; Ravaioli, Matteo; Battelli, Maria Giulia; Musiani, S; Grazi, Gian Luca

doi:10.1111/j.1572-0241.2002.05925.x

Cited by 65 publications

(40 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both ROS generation experiments and inhibition of HIF1-a induction by allopurinol provided evidence that XO was an important source of radical generation and may be relevant in the signaling pathway involving the HIF1-a induction in U251-MG cells. Although XO activity has been determined in a number of animal tumors and in a few human tumors (29)(30)(31)(32)(33)(34)(35)(36)(37), little is known about the expression Figure 2. A, DCF fluorescence as a measure of ROS generation.…”

Section: Resultsmentioning

confidence: 99%

Xanthine Oxidase–Dependent Regulation of Hypoxia-Inducible Factor in Cancer Cells

Griguer¹,

Oliva²,

Kelley

et al. 2006

Cancer Research

View full text Add to dashboard Cite

During chemical hypoxia induced by cobalt chloride (CoCl 2 ), hypoxia-inducible factor 1A (HIF1-A) mediates the induction of a variety of genes including erythropoietin and vascular endothelial growth factor. We used glioma cells with oxidative phosphorylation-dependent (D54-MG) and glycolytic-dependent (U251-MG) phenotypes to monitor HIF1-A regulation in association with redox responsiveness to CoCl 2 treatment. We showed that CoCl 2 increased xanthine oxidase (XO)-derived reactive oxygen species (ROS), which causes accumulation of HIF1-A protein in U251-MG cells. Under these conditions, blockade of XO activity by pharmacologic (N-acetyl-L-cysteine or allopurinol) or molecular (by small interfering RNA) approaches significantly attenuated HIF1-A expression. Exogenous H 2 O 2 stabilizes HIF1-A protein. XO was present in these cells and was the primary source of free radicals. We also showed higher XO activity in cells exposed to CoCl 2 compared with cells grown in normoxia. From the experiments shown here, we concluded that ROS were indeed generated in D54-MG cells exposed to CoCl 2 but it was unlikely that ROS participated in the hypoxic signal transduction pathways in this cell type. Possibly, cell type-dependent and stimulusdependent factors may control ROS dependency or redox sensitivity of HIF1-A and thus HIF1-A activation either directly or by induction of specific signaling cascades. Our findings reveal that XO-derived ROS is a novel and critical component of HIF1-A regulation in U251-MG cells, pointing toward a more general role of this transcription factor in

show abstract

Section: Resultsmentioning

confidence: 99%

Xanthine Oxidase–Dependent Regulation of Hypoxia-Inducible Factor in Cancer Cells

Griguer¹,

Oliva²,

Kelley

et al. 2006

Cancer Research

View full text Add to dashboard Cite

show abstract

“…Further research needs to be carried out to study whether XOR expression of the tumor may be related to the response to adjuvant therapy. Little is known about the expression of XOR in different types of human cancer, but the sparse data available suggest that XOR activity may decrease in malignant tumors because XOR expression was low or absent in six hepatocellular carcinomas (21) and in four invasive breast carcinomas studied (22). We found that XOR activity is absent in malignant cell lines originating from human breast carcinoma, including MPE-600 cells which have a relatively well-preserved original karyotype (23).…”

Section: Discussionmentioning

confidence: 99%

Down-Regulated Xanthine Oxidoreductase Is a Feature of Aggressive Breast Cancer

Linder

Lundin

Isola

et al. 2005

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA, and high-energy phosphates and also plays a role in milk lipid globule secretion. Given the strong and regulated expression of XOR in normal breast epithelium, and the previously shown alterations of its expression in experimental tumorigenesis, we hypothesized that XOR may be differentially expressed in breast cancer. Experimental Design: XOR expression was analyzed by immunohistochemistry in tissue microarray specimens of 1,262 breast cancer patients with a median follow-up of 9.5 years. Results: Expression of XOR was moderately decreased in 50% and undetectable in another 7% of the tumors. Decreased XOR expression was associated with poor histologic grade of differentiation, ductal and lobular histologic types, large tumor size, high number of positive axillary lymph nodes, and high cyclooxygenase-2 expression, but not with estrogen or progesterone receptor status, Ki-67, p53, or ERBB2 amplification. Absence of XOR expression was associated with unfavorable outcome, and patients with no XOR expression had more than twice the risk of distant recurrence as compared with those with a moderately decreased or normal expression (hazard ratio, 2.21; P < 0.0001). This was also true in patients with node-negative disease (hazard ratio, 2.75; P < 0.0001) as well as in patients with small (V1cm) tumors (hazard ratio, 3.09; P = 0.027). In a multivariate survival analysis, negative XOR emerged as an independent prognostic factor both in the entire series (P = 0.01) and among patients with nodenegative disease (P = 0.0009). Conclusion: Loss of XOR identifies breast cancer patients with unfavorable prognosis.

show abstract

“…levels of expression have been demonstrated in both infected experimental animals (3,16,18,(62)(63)(64) and humans (32,43,60). Moreover, a protective role of XOR is indicated by observations that specific inhibition of XOR can increase microbial activity (14,52,58,61,64).…”

mentioning

confidence: 97%