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- Öberg, Fredrik, et al.
(författare)
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Herbal melanin activates TLR4/NF-kappaB signaling pathway
- 2009
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Ingår i: Phytomedicine. - : Elsevier BV. - 0944-7113 .- 1618-095X. ; 16:5, s. 477-84
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Tidskriftsartikel (refereegranskat)abstract
- Expression of many pro-inflammatory cytokines is controlled by the NF-kappaB signaling pathway. NF-kappaB is induced by LPS through activation of TLR4. Melanins extracted from fungal, plant and human sources modulate cytokine production and activate NF-kappaB pathway. We showed that a herbal melanin (HM) from Nigella sativa L. modulates cytokine production and suggested it as a ligand for TLR4. In this study we investigated the possibility that the HM-induced cytokine production is via an NF-kappaB signaling pathway. We found that HM induced the degradation of IkappaBalpha, a key step in the activation of NF-kappaB. Moreover, addition of IkappaB kinase (IKK) specific inhibitors effectively inhibited the observed HM-induced production of IL-8 and IL-6 by TLR4-transfected HEK293 cells and THP-1 cells. Our results have also shown that HM induced cleavage of caspase 8, and that this cleavage was partially abrogated by IKK inhibitors. We suggest that HM can modulate the inflammatory response by inducing IL-8 and IL-6 production via TLR4-dependent activation of the NF-kappaB signaling pathway.
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- Agarwal, Prasoon, et al.
(författare)
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Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:6, s. 6809-6923
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
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- Alzrigat, Mohammad, et al.
(författare)
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EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:6, s. 10213-10224
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Tidskriftsartikel (refereegranskat)abstract
- Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
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- Alzrigat, Mohammad, et al.
(författare)
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The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:61, s. 103731-103743
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
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- Bahram, Fuad, et al.
(författare)
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Posttranslational regulation of Myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937 monoblasts
- 1999
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Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 93:11, s. 3900-3912
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factors of the Myc/Max/Mad network are important regulators of cell growth, differentiation, and apoptosis and are frequently involved in tumor development. Constitutive expression of v-Myc blocks phorbol ester (TPA)-induced differentiation of human U-937 monoblasts. However, costimulation with interferon-gamma (IFN-gamma) and TPA restores terminal differentiation and G1 cell-cycle arrest despite continuous expression of v-Myc. The mechanism by which TPA + IFN-gamma counteract v-Myc activity has not been unravelled. Our results show that TPA + IFN-gamma treatment led to an inhibition of v-Myc- and c-Myc-dependent transcription, and a specific reduction of v-Myc:Max complexes and associated DNA-binding activity, whereas the steady state level of the v-Myc protein was only marginally affected. In contrast, TPA + IFN-gamma costimulation neither increased the expression of Mad1 or other mad/mnt family genes nor altered heterodimerization or DNA-binding activity of Mad1. The reduced amount of v-Myc:Max heterodimers in response to treatment was accompanied by partial dephosphorylation of v-Myc and c-Myc. Phosphatase treatment of Myc:Max complexes lead to their dissociation, thus mimicking the effect of TPA + IFN-gamma. In addition to modulation of the expression of Myc/Max/Mad network proteins, posttranslational negative regulation of Myc by external signals may, therefore, be an alternative biologically important level of control with potential therapeutic relevance for hematopoietic and other tumors with deregulated Myc expression.
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- Botling, Johan, et al.
(författare)
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CD49f (alpha 6 integrin) and CD66a (BGP) are specifically induced by retinoids during human monocytic differentiation
- 1995
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Ingår i: Leukemia. - 0887-6924 .- 1476-5551. ; 9:12, s. 2034-41
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Tidskriftsartikel (refereegranskat)abstract
- Retinoic acid (RA) and 1,25(OH)2-cholecalciferol (VitD3) are potent regulators of normal and malignant myeloid cells. In the human monoblast cell line U-937 they induce terminal differentiation, and the resulting phenotypes display both common and distinct, inducer-specific, properties. This paper shows that in U-937 cells the two retinoids, all-trans and 9-cis RA, induced the expression of CD49f (alpha 6 integrin subunit) and CD66a (biliary glycoprotein, BGP) mRNA and protein. In contrast, expression of CD49f and CD66a was not found in untreated or VitD3-induced cells. Cytokine-induced modulation of CD49f and CD66a expression was restricted to the retinoid-induced U-937 cells. The retinoid specific induction of CD49f and CD66a was confirmed in the related monoblastic cell line THP-1. Human blood monocytes and the monocytic cell line Mono Mac 6 responded poorly to RA, with respect to the regulation of CD49f and CD66a expression, indicating that early monocytic precursors were targets for the retinoid-specific regulation. Thus, the expression of CD49f and CD66a is developmentally regulated and specifically induced by all-trans and 9-cis Ra in human monocytic cells.
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