TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma

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Abstract

Background

Disseminated soft tissue sarcoma still represents a therapeutic dilemma because effective cytostatics are missing. Therefore we tested TRAIL and Tarolidine (TRD), two substances with apoptogenic properties on human fibrosarcoma (HT1080).

Methods

Viability, apoptosis and necrosis were visualized by TUNEL-Assay and quantitated by FACS analysis (Propidiumiodide/AnnexinV staining). Gene expression was analysed by RNA-Microarray and the results validated for selected genes by rtPCR. Protein level changes were documented by Western Blot analysis. NFKB activity was analysed by ELISA and proliferation assays (BrdU) were performed.

Results and discussion

The single substances TRAIL and TRD induced apoptotic cell death and decreased proliferation in HT1080 cells significantly. Gene expression of several genes related to apoptotic pathways (TRAIL: ARHGDIA, NFKBIA, TNFAIP3; TRD: HSPA1A/B, NFKBIA, GADD45A, SGK, JUN, MAP3K14) was changed. The combination of TRD and TRAIL significantly increased apoptotic cell death compared to the single substances and lead to expression changes in a variety of genes ( HSPA1A/B, NFKBIA, PPP1R15A, GADD45A, AXL, SGK, DUSP1, JUN, IRF1, MYC, BAG5, BIRC3). NFKB activity assay revealed an antipodal regulation of the several subunits of NFKB by TRD and TRD+TRAIL compared to TRAIL alone.

Conclusion

TRD and TRAIL are effective to induce apoptosis and decrease proliferation in human fibrosarcoma. A variety of genes seems to be involved, pointing to the NFKB pathway as key regulator in TRD/TRAIL-mediated apoptosis.

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Most cited references 74

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TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB.

C Y Wang, M. W. Mayo, A S Baldwin (1996)

Many cells are resistant to stimuli that can induce apoptosis, but the mechanisms involved are not fully understood. The activation of the transcription factor nuclear factor-kappa B (NF-kappaB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound), was found to protect from cell killing. Inhibition of NF-kappaB nuclear translocation enhanced apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-kappaB. These results provide a mechanism of cellular resistance to killing by some apoptotic reagents, offer insight into a new role for NF-kappaB, and have potential for improvement of the efficacy of cancer therapies.

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Transcriptional regulation via the NF-kappaB signaling module.

A. Hoffmann, G Natoli, G Ghosh (2006)

Stimulus-induced nuclear factor-kappaB (NF-kappaB) activity, the central mediator of inflammatory responses and immune function, comprises a family of dimeric transcription factors that regulate diverse gene expression programs consisting of hundreds of genes. A family of inhibitor of kappaB (IkappaB) proteins controls NF-kappaB DNA-binding activity and nuclear localization. IkappaB protein metabolism is intricately regulated through stimulus-induced degradation and feedback re-synthesis, which allows for dynamic control of NF-kappaB activity. This network of interactions has been termed the NF-kappaB signaling module. Here, we summarize the current understanding of the molecular structures and biochemical mechanisms that determine NF-kappaB dimer formation and the signal-processing characteristics of the signaling module. We identify NF-kappaB-kappaB site interaction specificities and dynamic control of NF-kappaB activity as mechanisms that generate specificity in transcriptional regulation. We discuss examples of gene regulation that illustrate how these mechanisms may interface with other transcription regulators and promoter-associated events, and how these mechanisms suggest regulatory principles for NF-kappaB-mediated gene activation.

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Taurine: new implications for an old amino acid.

Angelo Levis, Eunkyue Park (2003)

Taurine is a semi-essential amino acid and is not incorporated into proteins. In mammalian tissues, taurine is ubiquitous and is the most abundant free amino acid in the heart, retina, skeletal muscle, brain, and leukocytes. In fact, taurine reaches up to 50 mM concentration in leukocytes. Taurine has been shown to be tissue-protective in many models of oxidant-induced injury. One possibility is that taurine reacts with hypochlorous acid, produced by the myeloperoxidase pathway, to produce the more stable but less toxic taurine chloramine (Tau-Cl). However, data from several laboratories demonstrate that Tau-Cl is a powerful regulator of inflammation. Specifically, Tau-Cl has been shown to down-regulate the production of pro-inflammatory mediators in both rodent and human leukocytes. Taurolidine, a derivative of taurine, is commonly used in Europe as an adjunctive therapy for various infections as well as for tumor therapy. Recent molecular studies on the function of taurine provide evidence that taurine is a constituent of biologic macromolecules. Specifically, two novel taurine-containing modified uridines have been found in both human and bovine mitochondria. Studies investigating the mechanism of action of Tau-Cl have shown that it inhibits the activation of NF-kappaB, a potent signal transducer for inflammatory cytokines, by oxidation of IkappaB-alpha at Met45. Key enzymes for taurine biosynthesis have recently been cloned. Cysteine sulfinic acid decarboxylase, a rate-limiting enzyme for taurine biosynthesis, has been cloned and sequenced in the mouse, rat and human. Another key enzyme for cysteine metabolism, cysteine dioxygenase (CDO), has also been cloned from rat liver. CDO has a critical role in determining the flux of cysteine between cysteine catabolism/taurine synthesis and glutathione synthesis. Taurine transporter knockout mice show reduced taurine, reduced fertility, and loss of vision due to severe apoptotic retinal degeneration. Apoptosis induced by amino chloramines is a current and important finding since oxidants derived from leukocytes play a key role in killing pathogens. The fundamental importance of taurine in adaptive and acquired immunity will be unveiled using genetic manipulation.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date Collection: 2008

Publication date (Electronic): 12 December 2008

Volume: 27

Issue: 1

Page: 82

Affiliations

[1 ]Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany

[2 ]Department of General and Visceral Surgery, St. Josef Hospital, Ruhr-University, Gudrunstraße 56, 44791 Bochum, Germany

[3 ]Department of Medicine II, St. Josef Hospital, Ruhr-University, Gudrunstraße 56, 44791 Bochum, Germany

[4 ]Institute for Cell Biology (Tumor Research), University of Duisburg-Essen, Virchowstraße 173 45122 Essen, Germany

Article

Publisher ID: 1756-9966-27-82

DOI: 10.1186/1756-9966-27-82

PMC ID: 2635882

PubMed ID: 19077262

SO-VID: 9d1a87f8-44b5-4713-9886-197ef33f0df1

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma

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Abstract

Background

Methods

Results and discussion

Conclusion

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Cancer Immunotherapy

Most cited references 74

TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB.

Transcriptional regulation via the NF-kappaB signaling module.

Taurine: new implications for an old amino acid.

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