Modulation of Antioxidant Enzyme Expression and Function by Estrogen

Strehlow, Kerstin; Rotter, Simone; Waßmann, Sven; Adam, Oliver; Grohé, Christian; Laufs, Kerstin; Böhm, Michael; Nickenig, Georg

doi:10.1161/01.res.0000082334.17947.11

Cited by 407 publications

(299 citation statements)

References 56 publications

(48 reference statements)

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“…Estrogen was shown to modulate SOD3 activity through mRNA stabilization in human circulating monocytes. 41 However, the functional importance of this SNP and another studied SOD3 rs699473 SNP is unknown and there are no published studies on the association of these SNPs with the prognosis of patients with any type of carcinoma. Moreover, our study did not find any association between SOD3 transcript levels and PFS.…”

Section: Cancer Geneticsmentioning

confidence: 99%

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

Hubackova

Václavíková

Ehrlichová

et al. 2011

Intl Journal of Cancer

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Associations of transcript levels of oxidative stress-modifying genes SOD2, SOD3, NQO1 and NQO2 and their functional single nucleotide polymorphisms (SNPs) rs4880, rs1799895, rs2536512, rs699473, rs1800566 and rs1143684 with prognosis of breast cancer patients were studied. SNPs were assessed by allelic discrimination in a cohort of 321 breast cancer patients from the Czech Republic. Transcript levels were determined by real-time polymerase chain reaction (PCR) with absolute quantification in tumor and adjacent non-neoplastic control tissues. Both genotypes and transcript levels were then compared with available clinical data on patients. Patients carrying low activity allele Leu in NQO2 rs1143684 had a greater incidence of stage 0 or I disease (i.e., better prognosis) than patients with the Phe/Phe genotype. This association was more evident in patients without expression of progesterone receptors (p 5 0.031). Patients carrying the Thr allele in SOD3 rs2536512 SNP had a significantly greater incidence of tumors expressing estrogen receptors than patients carrying the Ala/Ala genotype (p 5 0.007). SOD3 transcript level was significantly higher in grade 1 or 2 tumors than in grade 3 tumors (p 5 0.006). Patients carrying T allele in SOD3 rs699473 SNP had significantly poorer progression-free survival (PFS) than patients carrying the CC genotype (p 5 0.038). The same applied to the subgroup of patients treated by hormonal regimens (p 5 0.021). Patients carrying the high activity Ala/Ala genotype in SOD2 (rs4880) had significantly poorer PFS than Val allele carriers in the group treated by cyclophosphamide but not hormonal regimens (p 5 0.004). Our results suggest that NQO2, SOD2 and SOD3 may significantly modify prognosis of breast cancer patients and that their significance should be further characterized.Breast cancer is the most common cancer in women. In 2008, about 1,383,523 new cases of invasive breast cancer were diagnosed worldwide. 1 The necessity of treating such a large number of patients calls for efficient tools that can be used for subgrouping patients according to estimated prognosis. A different spectrum of treatment modalities with diverse mechanisms of action and adverse effects could then be offered to various prognostic groups. Besides well-established classical prognostic factors such as tumor size, nodal status, grading and expression of hormonal receptors, numerous biological molecules are under investigation as potential prognostic biomarkers in breast carcinomas.Excess of oxidative stress, mediated by reactive oxygen species, may cause cellular deregulation leading to cell apoptosis, 2 proliferation or tumor promotion. 3 Alkylation and topoisomerase poisoning present the major mechanisms of action of cyclophosphamide and anthracyclines, respectively. Oxidative stress represents an additional cytotoxic mechanism. 4,5 One of the initial molecules of oxidative stress, superoxide anion radical, is formed by the univalent reduction of triplet-state molecular oxygen. This process is mediated by e...

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Section: Cancer Geneticsmentioning

confidence: 99%

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

Hubackova

Václavíková

Ehrlichová

et al. 2011

Intl Journal of Cancer

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“…Many therapeutic approaches for CVD are based on antioxidants. Estrogen can act as an antioxidant by upregulating superoxide dismutase in vascular tissue, which contributes to improved clearance of superoxide ions (15). In addition to this genomic effect, structurally the estrogen molecule contains a proton in the hydroxyl group of its aromatic ring A, which can bind to and detoxify the superoxide ions (16).…”

Section: Estrogen As An Antioxidantmentioning

confidence: 99%

Estrogen is a modulator of vascular inflammation

2008

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SummaryVascular inflammation underlies the pathogenesis of atherosclerosis. Atherosclerotic changes in the vasculature lead to conditions such as coronary artery disease and stroke, which are the major causes of morbidity and mortality worldwide. Epidemiological studies in premenopausal women suggest a beneficial role for estrogen in preventing vascular inflammation and consequent atherosclerosis. However, the benefits of estrogen are absent or even reversed in older postmenopausal subjects. The modulation of inflammation by estrogen under different conditions might explain this discrepancy. Estrogen exerts its antiinflammatory effects on the vasculature through different mechanisms such as direct antioxidant effect, generation of nitric oxide, prevention of apoptosis in vascular cells and suppression of cytokines and the renin-angiotensin system. On the other hand, estrogen also elicits proinflammatory changes under certain conditions, which are less completely understood. Some of the mechanisms underlying a possible proinflammatory role for estrogen include increased expression of the proinflammatory receptor for advanced glycation end products, increased tyrosine nitration of cellular proteins, and generation of reactive oxygen species through an uncoupled eNOS. In this review, we have presented evidence for both antiinflammatory and proinflammatory pathways modulated by estrogen and how interactions among such pathways might determine the effects of estrogen on the vascular system. IUBMBIUBMB Life, 60(6): 376-382, 2008

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“…NAC has been widely studied in relation to its role in modifying the production of reactive oxygen species by a variety of cell types under physiological and pathophysiological conditions (12,15,16,18). In contrast, the response of the ROS production in luteal cells to NAC remained unknown.…”

Section: Discussionmentioning

confidence: 99%

N‐acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction

Löhrke

Weitzel

et al. 2010

Cytometry Pt A

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N-acetylcysteine (NAC) is known as an antioxidant and used for mucus viscosity reduction. However, this drug prevents or induces cell death depending on the cell type. The response of steroidogenic luteal cells to NAC is unknown. Our data shows that NAC can behave as an antioxidant or prooxidant in dependency on the concentration and mitochondrial energization. NAC elevated the flowcytometric-measured portion of hypodiploid (dying) cells. This rise was completely abolished by aurintricarboxylic acid, an inhibitor of topoisomerase II. NAC increased the secretion of nitric oxide and cellular nitrotyrosine. An image analysis indicated that cells pretreated with NAC and loaded with DHR showed a fluorescent structure probably elicited by the oxidative product of DHR, rhodamine 123 that sequesters mitochondrially. Pretreating luteal cells with NAC or adding NAC directly to mitochondrial fractions followed by assessing the mitochondrial transmembrane potential difference (Dw) by the JC-1 technique demonstrated a marked decrease in Dw. A protonophore restored Dw and rotenone (an inhibitor of respiratory chain complex I) inhibited mitochondrial recovering. Thus, in steroidogenic luteal cells from healthy mature corpus luteum, NAC impairs cellular survival by interfering with mitochondrial metabolism. The protonophoreinduced recovering of NAC-provoked decrease in Dw indicates that an ATP synthasefavored route of H 1 re-entry to the matrix is essentially switched off by NAC while other respiratory chain complexes remain intact. These data may be important for therapeutic timing of treatments with NAC. ' 2010 International Society for Advancement of Cytometry Key terms luteal cells; antioxidant; redox imbalance; dihydrorhodamine 123; flow cytometry; mitochondrial dysfunction; viability THE corpus luteum is a transient ovarian steroidogenic gland, which develops within few days from the ovulated follicle to establish embryonic development. Intense vascularization is essential for maturation and maintenance of a healthy gland (1,2). The mature mid-luteal phase corpus luteum secretes large quantities of progesterone, a derivative from its mitochondrially formed precursor, pregnenolone.Steroidogenesis-dependent oxy-radicals and oxidants are generated during intramitochondrial conversion of cholesterol through the activity of NADPH-dependent cholesterol monooxygenase (side chain cleaving). It catalyzes in a phospholipid-assisted manner the formation of pregnenolone. This process is accompanied by an electron leakage into the mitochondrial matrix (3) and the synthesis of 4-methylpental as byproduct (4,5). In addition, regulatory constituents driving enhanced steroidogenesis are generated by the cyclooxygenase and lipoxygenase pathways which require reactive oxygen species. For instance, cyclooxygenase has an absolute requirement for hydroperoxide to catalyze oxygenation of lipids with a lipoperoxidation as the first step in forming prostanoids (6). In turn, high concentration of antioxidants and oxidant-detoxifying enzym...

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Modulation of Antioxidant Enzyme Expression and Function by Estrogen

Cited by 407 publications

References 56 publications

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

Estrogen is a modulator of vascular inflammation

N‐acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction

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