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Dive into the research topics where Elin Hallan Naderi is active.

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Featured researches published by Elin Hallan Naderi.


Blood | 2009

Activation of cAMP signaling inhibits DNA damage-induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation

Elin Hallan Naderi; Harry W. Findley; Ellen Ruud; Heidi Kiil Blomhoff; Soheil Naderi

In lymphocytes, the second messenger cyclic adenosine monophosphate (cAMP) plays a well-established antiproliferative role through inhibition of G(1)/S transition and S-phase progression. We have previously demonstrated that, during S-phase arrest, cAMP inhibits the action of S phase-specific cytotoxic compounds, leading to reduction in their apoptotic response. In this report, we provide evidence that cAMP can also inhibit the action of DNA-damaging agents independently of its effect on S phase. Elevation of cAMP in B-cell precursor acute lymphoblastic leukemia cells is shown to profoundly inhibit the apoptotic response to ionizing radiation, anthracyclins, alkylating agents, and platinum compounds. We further demonstrate that this effect depends on the ability of elevated cAMP levels to quench DNA damage-induced p53 accumulation by increasing the p53 turnover, resulting in attenuated Puma and Bax induction, mitochondrial outer membrane depolarization, caspase activation, and poly(ADP-ribose) polymerase cleavage. On the basis of our findings, we suggest that cAMP levels may influence p53 function in malignant cells that retain wild-type p53, potentially affecting p53 both as a tumor suppressor during cancer initiation and maintenance, and as an effector of the apoptotic response to DNA-damaging agents during anticancer treatment.


Journal of Immunology | 2013

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Randi Larsen Indrevær; Kristine Lillebø Holm; Pål Aukrust; Liv T. Osnes; Elin Hallan Naderi; Børre Fevang; Heidi Kiil Blomhoff

Common variable immunodeficiency (CVID) is a disease that is characterized primarily by low levels of serum Igs, resulting in a high incidence of infections. It also has been associated with impaired B cell signaling via TLR9 and reduced serum levels of vitamin A. Given the established link between vitamin A deficiency and increased susceptibility to infections, we investigated the ability of the vitamin A metabolite all-trans retinoic acid (RA) to restore the defective immune responses in CVID-derived B cells activated through the TLRs TLR9 and RP105. We demonstrate that RA almost normalizes proliferation and IL-10 secretion in patient-derived B cells. IgG secretion is also partially restored, but to a more moderate extent. This can be explained by impaired RA-mediated isotype switching in TLR9/RP105-stimulated CVID-derived B cells owing to reduced induction of activation-induced deaminase. Accordingly, these B cells secreted higher levels of IgM than did normal B cells, and RA augmented IgM secretion. The ability of RA to improve critical immune parameters in CVID-derived B cells stimulated through TLR9 and RP105 support the possibility of combining RA with TLR stimulation for the treatment of CVID.


Molecular Cancer | 2015

Bone marrow stroma-derived PGE2 protects BCP-ALL cells from DNA damage-induced p53 accumulation and cell death

Elin Hallan Naderi; Seham Skah; Hege Grefslie Ugland; Ola Myklebost; Dagny Sandnes; Maria Lyngaas Torgersen; D. Josefsen; Ellen Ruud; Soheil Naderi; Heidi Kiil Blomhoff

BackgroundB cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. BCP-ALL blasts typically retain wild type p53, and are therefore assumed to rely on indirect measures to suppress transformation-induced p53 activity. We have recently demonstrated that the second messenger cyclic adenosine monophosphate (cAMP) through activation of protein kinase A (PKA) has the ability to inhibit DNA damage-induced p53 accumulation and thereby promote survival of the leukaemic blasts.Development of BCP-ALL in the bone marrow (BM) is supported by resident BM-derived mesenchymal stromal cells (MSCs). MSCs are known to produce prostaglandin E2 (PGE2) which upon binding to its receptors is able to elicit a cAMP response in target cells. We hypothesized that PGE2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells.MethodsPrimary BCP-ALL cells isolated from BM aspirates at diagnosis were cocultivated with BM-derived MSCs, and effects on DNA damage-induced p53 accumulation and cell death were monitored by SDS-PAGE/immunoblotting and flow cytometry-based methods, respectively. Effects of intervention of signalling along the PGE2-cAMP-PKA axis were assessed by inhibition of PGE2 production or PKA activity. Statistical significance was tested by Wilcoxon signed-rank test or paired samples t test.ResultsWe demonstrate that BM-derived MSCs produce PGE2 and protect primary BCP-ALL cells from p53 accumulation and apoptotic cell death. The MSC-mediated protection of DNA damage-mediated cell death is reversible upon inhibition of PGE2 synthesis or PKA activity. Furthermore our results indicate differences in the sensitivity to variations in p53 levels between common cytogenetic subgroups of BCP-ALL.ConclusionsOur findings support our hypothesis that BM-derived PGE2, through activation of cAMP-PKA signalling in BCP-ALL blasts, can inhibit the tumour suppressive activity of wild type p53, thereby promoting leukaemogenesis and protecting against therapy-induced leukaemic cell death. These novel findings identify the PGE2-cAMP-PKA signalling pathway as a possible target for pharmacological intervention with potential relevance for treatment of BCP-ALL.


Cancer Letters | 2013

Death of multiple myeloma cells induced by cAMP-signaling involves downregulation of Mcl-1 via the JAK/STAT pathway

Virginie Follin-Arbelet; Maria Lyngaas Torgersen; Elin Hallan Naderi; Kristine Misund; Anders Sundan; Heidi Kiil Blomhoff

There is a continuous search for new therapeutic targets for treatment of multiple myeloma (MM). Here we investigated the mechanisms involved in cAMP-induced apoptosis of human MM cells. cAMP-increasing agents rapidly inhibited activation of JAK1 and its substrate STAT3. In line with STAT3 being a regulator of Mcl-1 transcription, the expression of this pro-survival factor was rapidly and selectively reduced. Notably, exogenous interleukin-6 neither prevented the inhibition of JAK1/STAT3 nor the death of MM cells induced by cAMP. Our results suggest that cAMP-mediated killing of MM cells involves inhibition of the JAK/STAT pathway, making the cAMP-pathway a promising target for treatment of MM.


International Journal of Oncology | 2013

cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

Martine Müller Kloster; Elin Hallan Naderi; Ingvild Haaland; Bjørn Tore Gjertsen; Heidi Kiil Blomhoff; Soheil Naderi

Activation of cAMP signalling potently inhibits DNA damage-induced apoptosis in acute lymphoblastic leukemia cells by promoting the turnover of p53 protein. Recently, we showed that the cAMP-induced destabilization of p53 in DNA-damaged cells occurs as a result of enhanced interaction between p53 and HDM2. In this report, we present results showing that increased levels of cAMP in cells with DNA damage enhances the deacetylation of p53, an event that facilitates the interaction of p53 with HDM2, thus annulling the stabilizing effect of DNA damage on p53. The combined inhibition of the HDAC and SIRT1 deacetylases abolished the cAMP-mediated deacetylation of p53, implying that cAMP-mediated deacetylation of p53 is dependent on the activity of these two classes of histone deacetylases. Importantly, diminishing the activity of HDACs and SIRT1 was also found to reverse the inhibitory effect of cAMP on the DNA damage-induced p53 stabilization and apoptosis, suggesting the involvement of the p53 acetylation pathway in the anti-apoptotic effect of cAMP signalling.


Scientific Reports | 2015

The natural compound forskolin synergizes with dexamethasone to induce cell death in myeloma cells via BIM

Virginie Follin-Arbelet; Kristine Misund; Elin Hallan Naderi; Hege Katrin Ugland; Anders Sundan; Heidi Kiil Blomhoff

We have previously demonstrated that activation of the cyclic adenosine monophosphate (cAMP) pathway kills multiple myeloma (MM) cells both in vitro and in vivo. In the present study we have investigated the potential of enhancing the killing of MM cell lines and primary MM cells by combining the cAMP-elevating compound forskolin with the commonly used MM therapeutic drugs melphalan, cyclophosphamide, doxorubicin, bortezomib and dexamethasone. We observed that forskolin potentiated the killing induced by all the tested agents as compared to treatment with the single agents alone. In particular, forskolin had a synergistic effect on the dexamethasone-responsive cell lines H929 and OM-2. By knocking down the proapoptotic BCL-2 family member BIM, we proved this protein to be involved in the synergistic induction of apoptosis by dexamethasone and forskolin. The ability of forskolin to maintain the killing of MM cells even at lower concentrations of the conventional agents suggests that forskolin may be used to diminish treatment-associated side effects. Our findings support a potential role of forskolin in combination with current conventional agents in the treatment of MM.


Molecular Cancer | 2011

Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death

Martine Müller Kloster; Elin Hallan Naderi; Harald Carlsen; Heidi Kiil Blomhoff; Soheil Naderi

With cAMP signaling having a profound inhibitory effect on DNA damage-induced apoptosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells, understanding how this signaling pathway affects the survival capacity of the cell has important implications for cancer therapy. We have recently shown that p53 is critical for the inhibitory effect of cAMP on genotoxic agents-mediated apoptosis in BCP-ALLs. Here, we show that elevation of cAMP levels in cells exposed to DNA damage enhances the nuclear translocation and DNA binding of NF-κB by accelerating the phosphorylation of IKKβ and thereby phosphorylation and degradation of IκBα. Furthermore, we show that the ability of cAMP to potentiate the ionizing radiation-induced activation of NF-κB requires the activity of MEK. Importantly, pharmacological or genetic ablation of NF-κB reversed the inhibitory effect of cAMP on DNA damage-induced apoptosis, demonstrating that, in addition to p53, cAMP relies on the activity of NF-κB to provide cells with a survival advantage in the face of DNA damage. Collectively, our results uncover a novel and important interaction between the cAMP and NF-κB pathways that may have implications for the targeted treatment of lymphoid malignancies, such as BCP-ALL, in which aberrant NF-κB activity functions as a driving force for treatment resistance.


Cellular Signalling | 2008

EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase.

Martine Müller Kloster; Tilahun Tolesa Hafte; Lise Román Moltzau; Elin Hallan Naderi; Maria K. Dahle; Bjørn Steen Skålhegg; Gustav Gaudernack; Finn Olav Levy; Soheil Naderi; Heidi Kiil Blomhoff

Cyclic AMP (cAMP) is an important physiological growth inhibitor of lymphoid cells, and the cAMP/protein kinase A (PKA) pathway is disrupted in several immunological disorders and cancers. Epstein Barr virus (EBV) infection of B lymphocytes is responsible for the development of lymphoproliferative disease as well as certain B-lymphoid malignancies. Here we hypothesized that EBV infection might render B lymphocytes resistant to cAMP/PKA-mediated growth inhibition. To test this, we assessed the growth-inhibitory response of cAMP-elevating compounds such as forskolin and isoproterenol, as well as the PKA activator 8-CPT-cAMP in normal B lymphocytes, EBV-infected B cells and in the EBV-negative B lymphoid cell line Reh. We could demonstrate that EBV infection indeed abolished cAMP-mediated growth inhibition of B cells. The defect was pinpointed to defective adenylyl cyclase (AC) activation by forskolin and isoproterenol, resulting in reduced formation of cAMP and lack of PKA activation and CREB phosphorylation. In contrast, 8-CPT-cAMP which directly activates PKA was able to inhibit EBV-infected B cell growth. The physiological implications of these results were underlined by the observation that the ability of forskolin to inhibit camptothecin-induced apoptosis was abolished in EBV-infected B cells. We conclude that EBV infection of B cells abrogates the activation of AC and thereby cAMP formation, and that this dysfunction renders the cells resistant to growth inhibition via the cAMP/PKA pathway.


Blood | 2013

Selective inhibition of cell death in malignant vs normal B-cell precursors: implications for cAMP in development and treatment of BCP-ALL

Elin Hallan Naderi; Hege Katrin Ugland; Phoi-Phoi Diep; D. Josefsen; Ellen Ruud; Soheil Naderi; Heidi Kiil Blomhoff

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most commonly occurring pediatric cancer. Despite its relatively good prognosis, there is a steady search for strategies to improve treatment effects and prevent the undesired side effects on normal cells. In the present paper, we demonstrate a differential effect of cyclic adenosine monophosphate (cAMP) signaling between normal BCPs and BCP-ALL blasts, pointing to a potential therapeutic window allowing for manipulation of cAMP signaling in the treatment of BCP-ALL. By studying primary cells collected from pediatric BCP-ALL patients and healthy controls, we found that cAMP profoundly decreased basal and DNA damage-induced p53 levels and cell death in malignant cells, whereas normal BCP counterparts displayed slightly augmented cell death when exposed to cAMP-increasing agents. We did not find evidence for a selection process involving generation of increased basal cAMP levels in BCP-ALL cells, but we demonstrate that paracrine signaling involving prostaglandin E2-induced cAMP generation has the potential to suppress p53 activation and cell death induction. The selective inhibitory effect of cAMP signaling on DNA damage-induced cell death in BCP-ALL cells appears to be an acquired trait associated with malignant transformation, potentially allowing the use of inhibitors of this pathway for directed killing of the malignant blasts.


Immunology | 2016

Myeloid cell leukaemia 1 has a vital role in retinoic acid-mediated protection of Toll-like receptor 9-stimulated B cells from spontaneous and DNA damage-induced apoptosis.

Kristine Lillebø Holm; Randi Larsen Indrevær; June H. Myklebust; Arne Kolstad; Jan Øivind Moskaug; Elin Hallan Naderi; Heidi Kiil Blomhoff

Vitamin A is an essential anti‐infective agent with pleiotropic effects on cells of the immune system. The goal of the present study was to unravel the impact of the vitamin A metabolite retinoic acid (RA) on B‐cell survival related both to normal B‐cell homeostasis and to the detrimental effects imposed by DNA‐damaging agents. By combining RA with Toll‐like receptor 9 (TLR9) ligands, we show that RA prevents spontaneous, irradiation‐ and doxorubicin‐induced apoptosis of human B cells in an RA receptor‐dependent manner. RA‐mediated survival involved up‐regulation of the anti‐apoptotic protein myeloid cell leukemia 1 (MCL1) at the transcriptional level, and knock down of MCL1 by small interfering RNA partially reversed the effects of RA. To ensure that the combination of TLR9‐ligands and RA would not promote the survival of malignant B cells, the combined effects of stimulation with RA and TLR9 ligands was assessed on cells from patients with B‐cell malignancies. In contrast to the effects on normal B cells, the combination of TLR9 stimulation and RA neither enhanced the MCL1 levels nor inhibited the death of malignant B cells challenged by DNA‐damaging agents. Taken together, the present results reveal a vital role of MCL1 in RA‐mediated survival of normal B cells. Moreover, the findings suggest that RA in combination with TLR9 ligands might be useful adjuvants in the treatment of B‐cell malignancies by selectively protecting normal and not malignant B cells from DNA‐damage‐induced cell death.

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Ellen Ruud

Oslo University Hospital

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Anders Sundan

Norwegian University of Science and Technology

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D. Josefsen

Oslo University Hospital

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Kristine Misund

Norwegian University of Science and Technology

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