The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues

Perquin, Magali; Oster, Thierry; Maul, Armand; Froment, Nicolas; Untereiner, M.; Bagrel, Denyse

doi:10.1016/s0304-3835(00)00481-x

Cited by 36 publications

(30 citation statements)

References 17 publications

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“…Breast cancers have been described to display a deregulated glutathione peroxidation system (44,45). Therefore, we examined a panel of breast cancer cell lines for the expression of NPGPx.…”

Section: Lack Of Npgpx Expression In Breast Cancermentioning

confidence: 99%

Identification of a Novel Putative Non-selenocysteine Containing Phospholipid Hydroperoxide Glutathione Peroxidase (NPGPx) Essential for Alleviating Oxidative Stress Generated from Polyunsaturated Fatty Acids in Breast Cancer Cells

Utomo

Jiang

Furuta

et al. 2004

Journal of Biological Chemistry

109

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A dramatic reduction in the expression of a novel phospholipid hydroperoxide glutathione peroxidase (PHGPx), which incorporates cysteine instead of selenocysteine in the conserved catalytic motif was observed in a microarray analysis using cDNAs amplified from mRNA of Brca1-null mouse embryonic fibroblasts. This non-selenocysteine PHGPx named NPGPx is a cytoplasmic protein with molecular mass of ϳ22 kDa and has little detectable glutathione peroxidase activity in vitro. Ectopic expression of NPGPx in Brca1-null cells that were sensitive to oxidative stress induced by hydrogen peroxide conferred a similar resistance level to that of the wild-type cells, suggesting the importance of this protein in reducing oxidative stress. Expression of NPGPx was found in many tissues, including developing mammary gland. However, the majority of breast cancer cell lines studied (11 of 12) expressed very low or undetectable levels of NPGPx irrespective of BRCA1 status. Re-expression of NPGPx in breast cancer lines, MCF-7 and HCC1937, which have very little or no endogenous NPGPx, induced resistance to eicosapentaenoic acid (an omega-3 type of polyunsaturated fatty acid)-mediated cell death. Conversely, inhibition of the expression of NPGPx by the specific small interfering RNA in HS578T breast cancer cells that originally express substantial amounts of endogenous NPGPx increased their sensitivity to eicosapentaenoic acid-mediated cell death. Thus, NPGPx plays an essential role in breast cancer cells in alleviating oxidative stress generated from polyunsaturated fatty acid metabolism.

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Section: Lack Of Npgpx Expression In Breast Cancermentioning

confidence: 99%

Identification of a Novel Putative Non-selenocysteine Containing Phospholipid Hydroperoxide Glutathione Peroxidase (NPGPx) Essential for Alleviating Oxidative Stress Generated from Polyunsaturated Fatty Acids in Breast Cancer Cells

Utomo

Jiang

Furuta

et al. 2004

Journal of Biological Chemistry

109

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“…GST, by sulfhydrolizing electrophilic metabolic intermediates or drugs, acts as a housekeeping regulator of ROS homeostasis (32)(33)(34). Because maspin confers a higher cellular GST activity, it is possible that maspin expression may also affect ROS generation.…”

Section: The Effect Of Maspin/gst Interaction On Gst Activity and Rosmentioning

confidence: 99%

Tumor-suppressive Maspin Regulates Cell Response to Oxidative Stress by Direct Interaction with Glutathione S-Transferase

Meng

et al. 2005

Journal of Biological Chemistry

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Maspin, a novel serine protease inhibitor, suppresses tumor progression in several cancer models, including an in vivo model for prostate cancer bone metastasis. However, the molecular mechanism of maspin remains illusive, primarily because its molecular targets are unknown. To this end, we used a full-length maspin cDNA bait to screen against both a primary prostate tumor cDNA prey library and a HeLa cDNA prey library by the yeast two-hybrid method. We found that heat shock protein 90, glutathione S-transferase (GST), and heat shock protein 70 interacted with maspin with the highest frequencies. We confirmed the maspin/GST interaction using purified proteins, human epithelial cell lines, and human prostate tissues. A maspin variant that has a point mutation of Arg 340 to Ala (Mas R340A) showed a significantly decreased affinity for GST. Although purified maspin had no effect on the activity of purified GST in vitro, intracellular interaction between endogenous maspin and GST correlated with an elevated total GST activity in both MDA-MB-435-and DU145-derived stably transfected cells. Consistently, tumor cells treated with purified wild type maspin, but not Mas R340A, enhanced cellular GST activity. Maspin expression in cancer cell lines also correlated with decreased basal levels of reactive oxygen species (ROS). Furthermore, H 2 O 2 treatment not only induced GST expression but also increased intracellular maspin/ GST interaction, which was inversely correlated with the level of ROS generation. Conversely, maspin knockdown by small interfering RNA increased the basal, as well as H 2 O 2 -induced, ROS generation. Furthermore, the maspin effect on ROS generation was completely abolished by a GST inhibitor, indicating an essential role of GST in maspin-mediated cellular response to oxidative stress. Consistently, oxidative stress-induced vascular endothelial growth factor A expression was significantly inhibited in maspin-expressing cells. Together, our data suggest a new mechanism by which maspin, through its direct interaction with GST, may inhibit oxidative stress-induced ROS generation and vascular endothelial growth factor A induction, thus preventing further adverse effects on tumor genetics and stromal reactivity.Maspin, a novel serine protease inhibitor (serpin), 2 remains a promising potential therapeutic agent for a tumor suppressive effect in several cancer models (1-4). More recently, we showed that maspin expression inhibited prostate carcinoma bone tumor growth, osteolysis, and angiogenesis in a clinically relevant in vivo model (5). Consistently, differential expression of maspin has been linked to the progression of many types of human cancers. For example, in breast, colon, thyroid, lung, oral squamous, and prostate cancer, maspin expression predicts a better prognosis (6).Considering the therapeutic potential of maspin, it is critical to understand its molecular mechanisms. Three functional features of maspin are particularly noteworthy. First, an inhibitory effect of maspin on cell surface-assoc...

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“…Their ability to metabolise carcinogens and anticancer drugs lends them the potential to influence tumour development and sensitivity to chemotherapy and therefore tumour progression and treatment outcome [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Martínez

Kennedy

Doolan

et al. 2007

Breast Cancer Res Treat

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The complex role of drug metabolism-related enzymes and their possible influence in cancer development, treatment and outcome has not yet been completely elucidated. There is evidence that these enzymes can activate certain environmental procarcinogens to more toxic derivatives and thus a role has been proposed for them in carcinogenesis. The fact that they can also inactivate a number of chemotherapeutic drugs has raised the possibility of these enzymes influencing the sensitivity of tumour cells to anticancer agents. In this report, we analyse the expression of drug metabolism-related genes within a whole genome microarray study of 104 breast cancer and 17 normal breast specimens. Kaplan-Meier survival curves, Chi-squared, and Cox Regression analyses were used to identify associations between expression of gene transcripts and patients' clinicopathological and survival data. Our results show that several of these genes are significantly expressed in both normal and tumour tissue; in many cases, expression is altered in the tumour specimens as compared to normal breast tissue. Moreover, expression of ARNT2 and GST A1 was correlated with prognosis. Kaplan-Meier analysis showed expression of ARNT2 mRNA to correlate significantly with favourable disease outcome for patients, in terms of both their disease-free survival (P = 0.0094) and overall survival (P = 0.0018) times from diagnosis, while detection of GST A1 mRNA correlated with shortened disease-free survival (P = 0.0131) and overall survival (P = 0.0028). Multivariate analysis indicated GST A1 expression to be an independent prognostic factor for overall survival (P = 0.045). Our results suggest a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers.

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The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues

Cited by 36 publications

References 17 publications

Identification of a Novel Putative Non-selenocysteine Containing Phospholipid Hydroperoxide Glutathione Peroxidase (NPGPx) Essential for Alleviating Oxidative Stress Generated from Polyunsaturated Fatty Acids in Breast Cancer Cells

Identification of a Novel Putative Non-selenocysteine Containing Phospholipid Hydroperoxide Glutathione Peroxidase (NPGPx) Essential for Alleviating Oxidative Stress Generated from Polyunsaturated Fatty Acids in Breast Cancer Cells

Tumor-suppressive Maspin Regulates Cell Response to Oxidative Stress by Direct Interaction with Glutathione S-Transferase

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

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