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Studies on Redox-proteins and Cytokines in inflammation and Cancer
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The redox state in the cell plays a major role in determining vital functions and its major imbalance can lead to severe cell injury or death. Redox active proteins and cytokines involved in this process includes thioredoxin (Trx), protein disulfide isomerase (PDI), and tumor necrosis factor (TNF) superfamilies. Trx is a multipotent protein and key regulator of cellular redox balance operating in synergy with Trx reductase and NADPH (the Trx system). Trx has gene regulatory activity of several transcription factors. It also controls in a fascinating way redox-sensitive “on-off” decisions for apoptotic or hypertrophic pathways. Trx protects against H2O2 and TNFmediated cytotoxicity, a pathway in which TNF receptor-binding generates ROS. TNF is an autocrine growth factor and survival factor in vitro and in vivo for B-type of chronic lymphocytic leukemia (B-CLL) cells. The overall aim of this study was to investigate the importance of redox active proteins and cytokines in inflammation and cancer. We focused on: i) the role of Trx, TrxR, and selenium in carcinogenesis and in resistant cancer cells. ii) the importance of Trx in cancer cells and the redox regulation of TNF and its receptors TNFR1 and TNFR2. iii) the potential role of Trx as a key regulator in cellular redox balance, in the pathogenesis of cardiac dysfunction; its relationship to stress response parameters. iv) whether unmutated CLL (UCLL) responses to PKC and ROS pathways were different from mutated CLL (M-CLL) responses.

Our results demonstrate pronounced selective selenium-mediated apoptosis in therapy resistant cells and suggest that redox regulation through the Trx system is an important target for cancer therapy. Trx was strikingly elevated in heart failure cases compared with controls signifying an adaptive stress response that is higher the more severe the disease. TNF autocrine release was redox modulated and the TNF receptors interacted at the cell surface membrane with the redox-active PDI, which excerted a stringent redox-control of the TNFR signaling. The proliferative response as well as increase of autocrine TNF and Trx were higher in U-CLL than in M-CLL.

The overall conclusion of the four papers included in this thesis is that redox-active proteins and cytokines plays an important role in control and regulation of cancer and inflammation. Furthermore, redox regulation via thioredoxin by selenium, may offer novel treatment possibilities for resistant tumors disease.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi , 2007.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 994
Keyword [en]
Thioredoxin (Trx), Selenium, Tumor necrosis factor (TNF), Cancer, nflammation, oxidative stress, Protein-disulfide isomerase (PDI), Tumor necrosis factor receptor (TNFR)
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-8798ISBN: 978-91-85715-26-8 (print)OAI: oai:DiVA.org:liu-8798DiVA: diva2:23487
Public defence
2007-05-10, Linden, ingång 65, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-09-22
List of papers
1. Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the thioredoxin system.
Open this publication in new window or tab >>Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the thioredoxin system.
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2004 (English)In: Biochemical Pharmacology, ISSN 0006-2952, Vol. 67, no 3, 513-522 p.Article in journal (Refereed) Published
Abstract [en]

Selenium treatment of the doxorubicin-resistant cell line, U-1285dox, derived from human small cell carcinoma of the lung, resulted in massive apoptosis. This effect appeared maximal at 2 days after addition of selenite. The apoptosis was caspase-3 independent as revealed by Western blot analysis, activity measurement and by using caspase inhibitors. Induction of apoptosis was significantly more pronounced and occurred after addition of lower concentrations of selenite in the doxorubicin-resistant cells compared to the parental doxorubicin-sensitive cells. High levels of selenite caused necrosis in the doxorubicin-sensitive cells. Analysis of enzymatic activity (insulin reduction) of thioredoxin reductase (TrxR) and TrxR protein concentration, measured by ELISA, revealed increasing activity and protein levels after treatment with increasing concentrations of selenium. Maximum relative increase was induced up to 1 μM in both sublines and at this selenium level the concentrations of TrxR measured as insulin reducing activity or ELISA immunoreactivity were nearly identical. Increasing concentrations of selenite up to 10 μM resulted in increased activity and concentration of TrxR in the sensitive subline but decreasing levels in the resistant subline. The level of truncated Trx (tTrx) was higher in the resistant U-1285dox cells but the level did not change with increasing selenite concentrations. Our results demonstrate pronounced selective selenium-mediated apoptosis in therapy-resistant cells and suggest that redox regulation through the thioredoxin system is an important target for cancer therapy.

Keyword
Selenium, Apoptosis, Multi-drug resistance, Thioredoxin reductase, Thioredoxin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14425 (URN)10.1016/j.bcp.2003.09.021 (DOI)
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-09-22
2. Elevated circulating levels of thioredoxin and stress in chronic heart failure
Open this publication in new window or tab >>Elevated circulating levels of thioredoxin and stress in chronic heart failure
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2004 (English)In: European Journal of Heart Failure, ISSN 1388-9842, Vol. 6, no 7, 883-890 p.Article in journal (Refereed) Published
Abstract [en]

Background: Chronic heart failure (CHF) is a complex syndrome, in which reactive oxygen species and inflammatory cytokines are important stressors that contribute to the pathogenesis.

Aim: We have studied physiological stress response parameters in CHF, in particular the redox-active regulator thioredoxin.

Subjects: A case–control study was conducted including a consecutive sample of CHF patients (n=27) of NYHA class II and III; comparison control subjects (n=29) were recruited from an association for retired people.

Method: Baseline levels of Trx, lipid peroxides (oxidative stress), TNF and IL-6 cytokines, platelet-activation marker P-selectin, cortisol (as peripheral effector of HPA axis), and the potent antioxidant selenoprotein Trx-reductase were assessed.

Results: Mean (±S.E.M.) plasma levels of Trx were significantly higher in patients with CHF (32±3 ng/ml), than in the healthy subjects (12±3 ng/ml, P<0.0001). Trx levels increased in proportion to severity of disease (NYHA class III>NYHA class II) and degree of stress. Trx elevation correlated well with increased oxidative stress (lipid peroxides, P<0.0001), circulatory P-selectin (P<0.0001), morning level of free salivary cortisol (P=0.0002), and serum creatinine (P=0.0417), but not with pro-inflammatory cytokines TNF and IL-6.

Conclusion: Trx was strikingly elevated in heart failure cases compared with controls, signifying an adaptive stress response that is higher the more severe the disease.

Keyword
Thioredoxin, Oxidative stress, TNF, IL-6, Inflammation, Chronic heart failure
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14426 (URN)10.1016/j.ejheart.2004.03.003 (DOI)
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-09-22
3. Membrane protein disulfide isomerase regulates TNF-receptors 1 and 2 via direct molecular interaction: Redox-control of TNF autocrine loop in CLL
Open this publication in new window or tab >>Membrane protein disulfide isomerase regulates TNF-receptors 1 and 2 via direct molecular interaction: Redox-control of TNF autocrine loop in CLL
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14427 (URN)
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2010-01-13
4. Increased thioredoxin and TNF expression in unmutated CLL compared with mutated CLL cells after protein kinase C activation
Open this publication in new window or tab >>Increased thioredoxin and TNF expression in unmutated CLL compared with mutated CLL cells after protein kinase C activation
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14428 (URN)
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2010-01-13

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