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Sensitization to TRAIL-induced apoptosis in human neuroblastoma SK-N-AS cells by NF-kappa B inhibitors is dependent on reactive oxygen species (ROS)
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-0308-1964
2011 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 104, no 2, 459-472 p.Article in journal (Refereed) Published
Abstract [en]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a variety of cancer cell lines with almost no toxicity toward normal cells. However, many neuroblastoma cells acquire resistance to TRAIL by mechanisms that are poorly understood. The objective of this study was to investigate involvement of the transcription factor NF-kappa B in the resistance of human neuroblastoma SK-N-AS cells to TRAIL-induced apoptosis. We used five compounds previously reported to inhibit NF-kappa B activity. SN50, curcumin, oridonin, and pyrrolidine dithiocarbamate (PDTC) all sensitized cells to TRAIL-induced apoptosis. In contrast, N-alpha-tosyl-l-phenylalanyl chloromethyl ketone (TPCK) did not affect sensitivity to TRAIL, although reporter gene assay clearly showed inhibition of NF-kappa B activity. In addition, neither curcumin nor oridonin had any inhibitory effect on NF-kappa B activity at concentrations at which sensitization to TRAIL was observed. Instead, the free radical scavenger N-acetyl-l-cysteine (NAC) completely blocked the effect on TRAIL-induced apoptosis caused by curcumin, oridonin, and PDTC. Furthermore, exposure of SK-N-AS cells to H(2)O(2) could mimic the TRAIL-sensitizing effect of other agents. In conclusion, our results suggest that sensitization of neuroblastoma SK-N-AS cells to TRAIL-induced apoptosis is correlated with induction of reactive oxygen species (ROS) rather than inhibition of NF-kappa B.

Place, publisher, year, edition, pages
2011. Vol. 104, no 2, 459-472 p.
Keyword [en]
Apoptosis, Neuroblastoma, NF-kappa B, ROS, TRAIL
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-68003DOI: 10.1007/s11060-010-0516-yISI: 000294263800006OAI: oai:DiVA.org:su-68003DiVA: diva2:471970
Note

authorCount :2

Available from: 2012-01-03 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Regulation of apoptotic processes in neurodegeneration and cancer: In vitro studies on human neuroblastoma cells
Open this publication in new window or tab >>Regulation of apoptotic processes in neurodegeneration and cancer: In vitro studies on human neuroblastoma cells
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Apoptosis is a highly controlled process of cell death, which is vital for maintenance of all multicellular organisms. Aberrant regulation of apoptosis can give rise to pathological conditions such as neurodegenerative diseases and cancer. Here, we used different human neuroblastoma cell lines to study mechanisms that may be involved in either neurodegeneration or resistance to cancer treatment. First, we have designed and developed tau-anchored FRET sensors (tAFSs) for live cell imaging of local caspase activation. Using these sensors we showed that the Alzheimer’s disease related neurotoxic peptide, amyloid-β, induced a global activation of caspase-3 and -6, but not -9, in neuronally differentiated SH-SY5Y cells. We also investigated the possible role of NF-κB in the resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in different human neuroblastoma cell lines. While N-type SH-SY5Y and IMR32 cells were unaffected, S-type SK-N-AS cells were clearly sensitized to TRAIL by different NF-κB inhibitory agents. However, no correlation between NF-κB inhibition and sensitization to TRAIL could be observed. Instead, induction of reactive oxygen species (ROS) seemed to play a more important role. Furthermore, using tAFSs we also showed that TRAIL resistance in SK-N-AS cells is mainly due to incomplete activation of caspase-3, and could be reversed by different PKC inhibitors.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2012. 71 p.
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-79157 (URN)978-91-7447-553-1 (ISBN)
Public defence
2012-10-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Available from: 2012-09-27 Created: 2012-08-28 Last updated: 2012-09-05Bibliographically approved

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