Inhibition of Constitutively Activated Nuclear Factor-κB Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma
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Abstract
Aberrant signaling of the nuclear facotr (NF-κB) pathway has been identified as a mediator of survival and apoptosis resistance in leukemias and lymphomas. Here, we report that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-κB pathway is independent of caspases or classic death receptors. We found that free intracellular iron and reactive oxygen species (ROS) are the main mediators of this cell death. Antioxidants such as N-Acetyl-l-cysteine and glutathione or the iron chelator desferrioxamine effectively block cell death in cutaneous T-cell lymphoma cell lines or primary T cells from Sézary patients. We show that inhibition of constitutively active NF-κB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. Furthermore, direct down-regulation of FHC by siRNA caused a ROS-dependent cell death. Finally, high concentrations of ROS induce cell death of malignant T cells. In contrast, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-κB inhibition. In addition, in a murine T-cell lymphoma model, we show that inhibition of NF-κB and subsequent down-regulation of FHC significantly delays tumor growth in vivo. Thus, our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-κB signaling. [Cancer Res 2009;69(6):2365–74]
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Several cancers, including breast, prostate and lymphoma, reprogram iron metabolism by increasing iron uptake or reducing iron export and storage.
“reprogramming of iron metabolism can occur via a variety of mechanisms, including the upregulation of several iron-intake pathways or downregulation of iron export and storage pathways in various types of cancer such as breast, prostate and lymphoma37,38.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [38]
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- Authors
- Kiessling, M. K., Klemke, C. D., Kamiński, M. M., Galani, I. E., Krammer, P. H., & Gülow, K.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- 1Tumor Immunology Program, German Cancer Research Center (DFKZ), Heidelberg, Germany and
- Venue
- Cancer Research
- Published
- 2009-03-15
- Volume
- 69
- Issue
- 6
- Pages
- 2365-2374
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1974679488
- Cited by
- 115
- References
- 50
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 8 · 2016: 12 · 2015: 8 · 2014: 12 · 2013: 7 · 2012: 4
- FWCI
- 11.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- cutaneous T-cell lymphoma, NF-κB signaling, FTH1, reactive oxygen species, intracellular iron, iron chelation, deferoxamine, N-acetylcysteine, glutathione, apoptosis-independent cell death, Sézary syndrome, tumor growth inhibition, therapeutic target
- MeSH terms
- Animals, Apoferritins, Ferrous Compounds, Humans, Iron, Mice, Inbred C57BL, Peptides, Sezary Syndrome, Skin Neoplasms, T-Lymphocytes, Signal Transduction, Down-Regulation, NF-kappa B, Lymphoma, T-Cell, Cutaneous, Cell Death, Reactive Oxygen Species, Oxidative Stress, RNA, Small Interfering, Cell Line, Tumor, Mice
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