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Eriksson, David
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Publications (10 of 11) Show all publications
Lindgren, T., Stigbrand, T., Råberg, A., Riklund, K., Johansson, L. & Eriksson, D. (2015). Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT116 p53 +/+ and HCT116 p53 -/- colorectal carcinoma cell lines. International Journal of Radiation Biology, 91(1), 99-111
Open this publication in new window or tab >>Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT116 p53 +/+ and HCT116 p53 -/- colorectal carcinoma cell lines
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2015 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 91, no 1, p. 99-111Article in journal (Refereed) Published
Abstract [en]

Purpose : To study the kinetics of gene expression alterations following radiation exposure of isogenic HCT116 p53+/+ and HCT116 p53-/- cell lines. Materials and methods : Cells were exposed to 5 Gy of irradiation (Cs-137) and genome-wide temporal expression analysis using Illumina bead chip arrays was performed. Signalling pathways were explored using Metacore (Genego). Biological responses including cell cycle checkpoint activation, centrosome amplification and senescence induction were analyzed. Results : Significant differences in the radiation response were observed between the p53+/+ and the p53-/- cell lines. In p53+/+ cells concurrent G1- and G2-arrests were activated followed by senescence induction. Increased expression of genes associated with senescence, senescence associated secretory phenotype (SASP) and repression of genes essential for G2-M transition were detected. P53-/- cells arrested mainly in G2 followed by centrosome amplification, mitotic slippage and a subsequent increase of polyploid cells. Furthermore, changes in expression correlated well with these signs of mitotic catastrophe. Conclusions : The presence or absence of p53 triggers different signalling cascades with different endpoints. Elucidating these differences is important as it enables improvement of radiation treatment and could be used to develop new combination treatments with specific inhibitors of key regulators of these cell death modalities.

Keywords
radiation, gene expression, senescence, p53, mitotic catastrophe, cell cycle checkpoint
National Category
Cell and Molecular Biology
Research subject
Immunology; radiation physics
Identifiers
urn:nbn:se:umu:diva-80231 (URN)10.3109/09553002.2015.959668 (DOI)000349557900011 ()25219679 (PubMedID)
Note

Originally published in manuscript form.

Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2018-06-08Bibliographically approved
Lindgren, T., Stigbrand, T., Johansson, L., Riklund, K. & Eriksson, D. (2014). Alterations in Gene Expression During Radiation-Induced Mitotic Catastrophe in He La Hep2 Cells. Anticancer Research, 34(8), 3875-3880
Open this publication in new window or tab >>Alterations in Gene Expression During Radiation-Induced Mitotic Catastrophe in He La Hep2 Cells
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2014 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, no 8, p. 3875-3880Article in journal (Refereed) Published
Abstract [en]

Aim: To explore kinetic changes in the gene expression profile during radiation-induced mitotic catastrophes. Materials and Methods: Gene expression changes were measured in HPV-infected HeLa Hep2 tumor cells following exposure to 5 Gy of ionizing radiation (Co-60). Signaling pathways were explored and correlated to the biological responses linked to mitotic catastrophe. Results: Following irradiation a transient G(2)-arrest was induced. Anaphase bridge formation and centrosome hyperamplification was observed. These phenotypical changes correlated well with the observed gene expression changes. Genes with altered expression were found to be involved in mitotic processes as well as G(2)- and spindle assembly checkpoints. Also centrosome-associated genes displayed an increased expression. Conclusion: This study elucidates specific characteristics in the altered gene expression pattern induced by irradiation, which can be correlated to the events of mitotic catastrophe in HeLa Hep2 cells. Therapeutic strategies modulating these alterations might potentiate future therapy and enhance tumor cell killing.

Place, publisher, year, edition, pages
INT INST ANTICANCER RESEARCH, 2014
Keywords
Radiation, cell cycle checkpoint, cell death, mitotic catastrophe, gene expression
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-92927 (URN)000339773400002 ()
Available from: 2014-09-18 Created: 2014-09-09 Last updated: 2018-06-07Bibliographically approved
Lindgren, T., Stigbrand, T., Riklund, K., Johansson, L. & Eriksson, D. (2012). Gene expression profiling in MOLT-4 cells during gamma-radiation-induced apoptosis. Tumor Biology, 33(3), 689-700
Open this publication in new window or tab >>Gene expression profiling in MOLT-4 cells during gamma-radiation-induced apoptosis
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2012 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, p. 689-700Article in journal (Refereed) Published
Abstract [en]

This study aims to identify the temporal changes in gene expression in MOLT-4, a leukemia cell line, in response to radiation and to present a comprehensive description of the pathways and processes that most significantly relate to the cellular biological responses. A global gene expression profile of 24,500 genes was performed on MOLT-4 tumor cells following exposure to 5 Gy of ionizing radiation (Co-60) using a bead chip array (Illumina). Signaling pathways and processes significantly altered following irradiation were explored using MetaCore. Cellular viability [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], activation of cell cycle checkpoints [fluorescence activated cell sorting (FACS)], and induction of apoptosis (FACS, caspase assays) were evaluated to correlate these biological responses to the gene expression changes. Totally, 698 different genes displayed a significantly altered expression following radiation, and out of these transcripts, all but one showed increased expression. One hour following irradiation, the expression was changed only for a few genes. Striking changes appeared at later time-points. From 3 to 24 h post-irradiation, a significant fraction of the genes with altered expression were found to be involved in cell cycle checkpoints and their regulation (CDKN1A), DNA repair (GADD45A, DDB2, XPC), apoptosis induction (DR5, FasR, Apo-2L, Bax), and T-cell activation/proliferation (CD70, OX40L). Irradiated MOLT-4 cells were arrested at the G2-checkpoint, followed by a decrease in cell viability, most pronounced 48 h after exposure. The cell death was executed by induced apoptosis and was visualized by an increase in subG1 cells and an increased activation of initiator (caspase-8 and caspase-9) and execution (caspase-3) caspases. Activation of cell cycle arrest and apoptosis correlated well in time with the changes in gene expression of those genes important for these biological processes. Activation of the apoptotic signaling pathways in MOLT-4 cells following irradiation includes components from the intrinsic as well as the extrinsic apoptotic pathways. This study indicates that the altered gene expression pattern induced by irradiation is important for the sequential steps observed in MOLT-4 cells during apoptosis induction.

Keywords
Apoptosis, Radiation, Gene expression, Leukemia, Microarray
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-56209 (URN)10.1007/s13277-012-0329-z (DOI)000303530200013 ()
Available from: 2012-06-12 Created: 2012-06-12 Last updated: 2018-06-08Bibliographically approved
Lindgren, T., Stigbrand, T., Raberg, A., Riklund, K., Johansson, L. & Eriksson, D. (2012). Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT 116 cell lines. Paper presented at 40th Congress of the International-Society-of-Oncology-and-Biomarkers, OCT 13-17, 2012, Jerusalem, ISRAEL. Tumor Biology, 33(Suppl. 1), 76-76
Open this publication in new window or tab >>Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT 116 cell lines
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2012 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no Suppl. 1, p. 76-76Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-61570 (URN)000309547800115 ()
Conference
40th Congress of the International-Society-of-Oncology-and-Biomarkers, OCT 13-17, 2012, Jerusalem, ISRAEL
Available from: 2012-11-28 Created: 2012-11-20 Last updated: 2018-06-08Bibliographically approved
Blomberg, J., Höglund, A., Eriksson, D., Ruuth, K., Jacobsson, M., Nilsson, J. & Lundgren, E. (2011). Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line. Apoptosis (London), 16(8), 783-794
Open this publication in new window or tab >>Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α in a resistant variant of the human U937 cell line
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2011 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 16, no 8, p. 783-794Article in journal (Refereed) Published
Abstract [en]

Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.

Keywords
Apoptosis, Death receptor, Resistance, Fas, Interferon, cFLIP
National Category
Biophysics Cell and Molecular Biology Medical and Health Sciences Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-3478 (URN)10.1007/s10495-011-0606-0 (DOI)
Available from: 2008-09-22 Created: 2008-09-22 Last updated: 2018-06-09Bibliographically approved
Eriksson, D. & Stigbrand, T. (2010). Radiation-induced cell death mechanisms. Tumor Biology, 31(4), 363-372
Open this publication in new window or tab >>Radiation-induced cell death mechanisms
2010 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 31, no 4, p. 363-372Article in journal (Refereed) Published
Abstract [en]

The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. One approach to achieve this is by inducing tumor cell apoptosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. It has become obvious in the last few years that inhibition of the proliferative capacity of malignant cells following irradiation, especially with solid tumors, can occur via alternative cell death modalities or permanent cell cycle arrests, i.e., senescence. In this review, apoptosis and mitotic catastrophe, the two major cell deaths induced by radiation, are described and dissected in terms of activating mechanisms. Furthermore, treatment-induced senescence and its relevance for the outcome of radiotherapy of cancer will be discussed. The importance of p53 for the induction and execution of these different types of cell deaths is highlighted. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation. Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.

Keywords
Radiation, Therapy, Apoptosis, Senescence, Mitotic catastrophe, p53
Identifiers
urn:nbn:se:umu:diva-41987 (URN)10.1007/s13277-010-0042-8 (DOI)000283439000016 ()20490962 (PubMedID)
Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2018-06-08Bibliographically approved
Eriksson, D., Löfroth, P.-O., Johansson, L., Riklund, K. & Stigbrand, T. (2009). Apoptotic signalling in HeLa Hep2 cells following 5 Gy of cobalt-60 gamma radiation. Anticancer Research, 29(11), 4361-4366
Open this publication in new window or tab >>Apoptotic signalling in HeLa Hep2 cells following 5 Gy of cobalt-60 gamma radiation
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2009 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 11, p. 4361-4366Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The apoptotic signalling pathways involved in the delayed type of apoptosis occurring in HeLa Hep2 cells following radiation were investigated. MATERIALS AND METHODS: HeLa Hep2 cells were exposed to 5 Gy of cobalt-60 radiation. The activation of caspase-2, caspase-8, caspase-9 and effector caspase-3 was investigated by caspase assay plates and Western blots. Cleavage of poly (ADP-ribose) polymerase (PARP) was analysed on Western blots. HeLa Hep2 cells were irradiated with or without preincubation with inhibitors of protein synthesis (cycloheximide, CHX) and caspases, followed by TUNEL staining and caspase assay plate evaluation. RESULTS: Initiator caspases-2, -8, -9, and effector caspase-3, were found to be activated and PARP cleaved following irradiation. CHX completely inhibited the caspase activation and the associated apoptosis. Pretreatment with caspase-2 inhibitor indicated that caspase-2 was involved in the execution of the apoptosis. CONCLUSION: Activation of the apoptotic signalling pathways following irradiation of HeLa Hep2 cells includes components from the intrinsic as well as the extrinsic pathways and seems to require de novo protein synthesis.

Keywords
Radiation, apoptosis, caspase-2, caspase-8, caspase-9
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-30615 (URN)20032379 (PubMedID)
Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2018-06-08Bibliographically approved
Eriksson, D., Blomberg, J., Lindgren, T., Löfroth, P.-O., Johansson, L., Riklund, K. & Stigbrand, T. (2008). Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells. Cancer Biotherapy and Radiopharmaceuticals, 23(5), 541-549
Open this publication in new window or tab >>Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells
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2008 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 23, no 5, p. 541-549Article in journal (Refereed) Published
Abstract [en]

Iodine-131 (131I) has been used both in unconjugated form and conjugated to antibody derivates (i.e., radioimmunotherapy; RIT) to treat malignant diseases. The mechanisms by which 131I-irradiation causes growth retardation are, however, inadequately understood. The aim of this study was to elucidate the sequential molecular and cellular events that initiate cell death in HeLa Hep2 cells exposed to 131I. In this paper, HeLa Hep2 cells were found to display a transient G2-M arrest following irradiation, but then reentered the cell cycle still containing unrepaired cellular damage. An increase of multipolar mitotic spindles, as well as a significant increase in centrosome numbers from 8.8% +/- 1.9% in controls to 54.7% +/- 2.2% in irradiated cells, was observed (p < 0.0001). A subsequent failure of cytokinesis caused the cells to progress into mitotic catastrophe. This was accompanied by the formation of giant cells with multiple nuclei, multilobulated nuclei, and an increased frequency of polyploidy cells. A fraction of the cells also displayed apoptotic features, including the activation of initiator caspases-2, -8, -9, and effector caspase-3, as well as cleavage of poly(ADP-ribose) polymerase, a cell-death substrate for active caspase-3. These findings demonstrate that mitotic catastrophes and the activation of a delayed type of apoptosis might be important mechanisms involved in cell death following the RIT of solid tumors with -emitting radionuclides, such as 131I.

Keywords
iodine-131, mitotic catastrophe, apoptosis, caspases, centrosomes, radioimmunotherapy
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-21104 (URN)10.1089/cbr.2007.0471 (DOI)18986216 (PubMedID)
Available from: 2009-04-06 Created: 2009-04-02 Last updated: 2018-06-09Bibliographically approved
Eriksson, D., Löfroth, P.-O., Johansson, L., Åhlström Riklund, K. & Stigbrand, T. (2007). Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 Gy of ionizing radiation.. Clin Cancer Res, 13(18 Pt 2), 5501s-5508s
Open this publication in new window or tab >>Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 Gy of ionizing radiation.
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2007 (English)In: Clin Cancer Res, ISSN 1078-0432, Vol. 13, no 18 Pt 2, p. 5501s-5508sArticle in journal (Refereed) Published
Abstract [en]

PURPOSE: Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The purpose of this study was to elucidate the sequential molecular and cellular events occurring in HeLa Hep2 cells exposed to such doses. METHODS: Dose-response curves, activation of cell cycle checkpoints, and mitotic behavior were investigated in HeLa Hep2 cells following 2.5- to 10-Gy irradiation by carrying out 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Western blots, fluorescence-activated cell sorting analysis, and immunofluorescence stainings. Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining was used to detect apoptosis. RESULTS: A G2-M arrest was shown by fluorescence-activated cell sorting analysis. p53 and p21 were found to be up-regulated but were not immediately related to the arrest. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage. This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with alpha-tubulin and gamma-tubulin antibodies. Furthermore, a dose-dependent significant increase in centrosome numbers from 12.6+/-6.6% to 67+/-5.3% was identified as well as a dose-dependent increase of polyploid cells from 2.8+/-1.3% to 17.6+/-2.1% with the highest absorbed dose of 10 Gy. These disturbances caused the cells to progress into mitotic catastrophe and a fraction of these dying cells showed apoptotic features as displayed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining 5 to 7 days after irradiation. CONCLUSION: An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep2 cells into mitotic catastrophe and delayed apoptosis. These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors.

Identifiers
urn:nbn:se:umu:diva-17688 (URN)10.1158/1078-0432.CCR-07-0980 (DOI)17875782 (PubMedID)
Available from: 2007-11-15 Created: 2007-11-15 Last updated: 2018-06-09Bibliographically approved
Erlandsson, A., Eriksson, D., Johansson, L., Riklund, K., Stigbrand, T. & Sundström, B. E. (2006). In vivo clearing of idiotypic antibodies with antiidiotypic antibodies and their derivatives. Molecular Immunology, 43(6), 599-606
Open this publication in new window or tab >>In vivo clearing of idiotypic antibodies with antiidiotypic antibodies and their derivatives
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2006 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 43, no 6, p. 599-606Article in journal (Refereed) Published
Abstract [en]

At immunolocalization of experimental tumors, idiotypic monoclonal antibodies, such as TS1 against cytokeratin 8, can be used to carry and deposit in vivo terapeutics in the tumor. These carriers also remain in the circulation and may cause negative side-effects in other tissues. In this report, several derivatives of the antiidiotypic antibody alphaTS1 were produced and tested for their clearing capacity of the idiotypic carrier antibody TS1. Intact monoclonal alphaTS1, scFv of a alphaTS1 and alphaTS1 Fab'2 and fragments were produced by recombinant technology or by cleavage with Ficin. The scFv was tailored by use of the variable domain genes of the light and heavy chain from the hybridoma clone in combination with a (Gly4Ser)3-linker, followed by expression in E. coli. When tested for clearing capacity, the intact divalent antiidiotypic IgG was found to be the most efficient. The divalent and the monovalent Fab fragment also demonstrated significant clearing, but lower than the intact antiidiotypic IgG. The alphaTS1 scFv antibody when injected separately was not found to clear the idiotype, but could do so when preincubated with the idiotype. Rapid excretion and in vivo instability of this low molecular weight antibody fragment may be the major reasons. Similar results were obtained when the system was reversed and the 131I-labeled antiidiotype IgG was cleared with the idiotype fragment. It is concluded that both intact antiidiotypic IgG, and Fab'2 fragments are able to clear the idiotypic antibodies. The experimental data support the conclusion that the Fc parts from both the idiotype and the antiidiotype may contribute to this elimination.

Identifiers
urn:nbn:se:umu:diva-13533 (URN)10.1016/j.molimm.2005.04.019 (DOI)15978666 (PubMedID)
Available from: 2007-02-23 Created: 2007-02-23 Last updated: 2018-06-09Bibliographically approved
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