Chromosome instability in diffuse large <scp>B</scp> cell lymphomas is suppressed by activation of the noncanonical <scp>NF</scp>‐κ<scp>B</scp> pathway

Ramachandiran, Sampath; Adon, Arsene M.; Guo, Xiangxue; Wang, Yi; Wang, Huichen; Chen, Zhengjia; Kowalski, Jeanne; Sunay, U. R.; Young, Andrew N.; Brown, Theresa C.; Mar, Jessica C.; Du, Yuhong; Fu, Haian; Mann, Karen P.; Natkunam, Yasodha; Boise, Lawrence H.; Saavedra, Harold I.; Lossos, Izidore S.; Bernal‐Mizrachi, Leon

doi:10.1002/ijc.29301

Cited by 17 publications

(17 citation statements)

References 48 publications

(70 reference statements)

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“…Extranodal MZL, characterized by t(11;18)(q21;q21)/API2-MALT, depends on NF-κB to inhibit DNA damage-induced and p53-mediated apoptosis [68]. In ABC-DLBCL, NF-κB binds to the promoter regions of GADD45α and REDD1 and regulates these molecules through collaborating with p53 to mediate cyclin G2 expression, suggesting a central role for NF-κB in maintaining genomic integrity and prevention of apoptosis [69]. …”

Section: Nf-κb Signaling and Apoptotic Pathwaysmentioning

confidence: 99%

NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms

Medeiros

et al. 2017

Blood Reviews

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The NF-κB pathway, a critical regulator of apoptosis, plays a key role in many normal cellular functions. Genetic alterations and other mechanisms leading to constitutive activation of the NF-κB pathway contribute to cancer development, progression and therapy resistance by activation of downstream anti-apoptotic pathways, unfavorable microenvironment interactions, and gene dysregulation. Not surprisingly, given its importance to normal and cancer cell function, the NF-κB pathway has emerged as a target for therapy. In the review, we present the physiologic role of the NF-κB pathway and recent advances in better understanding of the pathologic roles of the NF-κB pathway in major types of lymphoid neoplasms. We also provide an update of clinical trials that use NF-κB pathway inhibitors. These trials are exploring the clinical efficiency of combining NF-κB pathway inhibitors with various agents that target diverse mechanisms of action with the goal being to optimize novel therapeutic opportunities for targeting oncogenic pathways to eradicate cancer cells.

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Section: Nf-κb Signaling and Apoptotic Pathwaysmentioning

confidence: 99%

NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms

Medeiros

et al. 2017

Blood Reviews

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“…Nuclear factor-κB (NF-κB) is an important signal transduction pathway associated with cell proliferation, apoptosis, tumor treatment, and immune regulation (2)(3)(4). Abnormal activation of NF-κB signal transduction is considered a significant feature of DLBCL (5)(6)(7), and was found to be correlated with many clinicopathological features, prognosis and response to therapy in lymphomas.…”

Section: Introductionmentioning

confidence: 99%

PMA/IONO affects diffuse large B-cell lymphoma cell growth through upregulation of A20 expression

Yang

et al. 2016

Oncology Reports

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Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin lymphoma. A20 and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) are known to be related to DLBCL pathogenesis and progression. This study aimed to assess the effects of phorbol myristate acetate/ionomycin (PMA/IONO) on the growth and apoptosis of the DLBCL cell line OCI-LY1, and their associations with A20, MALT1 and survivin levels. Cell viability was assessed by MTT assay. Cell cycle distribution and apoptosis were evaluated using flow cytometry after incubation with Annexin V-FITC/propidium iodide (PI) and RNase/PI, respectively. Gene and protein expression levels were determined by quantitative real-time PCR and western blotting, respectively. To further determine the role of A20, this gene was silenced in the OCI-LY1 cell line by specific siRNA transfection. A20 protein levels were higher in the OCI-LY1 cells treated with PMA/IONO compared with the controls, and were positively correlated with the concentration and treatment time of IONO, but not with changes of PMA and MALT1. Meanwhile, survivin expression was reduced in the OCI-LY1 cells after PMA/IONO treatment. In addition, OCI-LY1 proliferation was markedly inhibited, with a negative correlation between cell viability and IONO concentration. In concordance, apoptosis rates were higher in the OCI-LY1 cells after PMA + IONO treatment. Cell cycle distribution differed between the OCI-LY1 cells with and without PMA/IONO treatment only at 24 h, with increased cells in the G0/G1 stage after PMA/IONO treatment. These findings indicate that PMA/IONO promotes the apoptosis and inhibits the growth of DLBCL cells, in association with A20 upregulation. Thus, A20 may be a potential therapeutic target for DLBCL.

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“…The Tyr42-phosphorylated IkBa may not be degraded and is bound to the SH2 domain of the regulatory PI3K subunit p85, thus unmasking NF-kB and allowing it to translocate to the nucleus (19). Doxorubicin and H 2 O 2 , atypical NF-kB activators, potentially induce REDD-1 expression (8,35), suggesting that REDD-1 is involved in the proteolysis-independent activation of NF-kB. Concordantly, our data showed that REDD-1 did not induce proteasomal degradation of IkBa and its phosphorylation at Tyr42, but rather stimulated phosphorylation at Ser536 and Ser276 of the NF-kB p65 liberated from IkBa.…”

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confidence: 99%

REDD‐1 aggravates endotoxin‐induced inflammationVIAatypical NF‐κB activation

Lee

Kim

et al. 2018

FASEB j.

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Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1 macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-κB activation was independent of 2 classic IKK-dependent NF-κB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IκBα, to elicit atypical NF-κB activation during the delayed and persistent phases of inflammation after stimulation. Moreover, REDD-1 knockdown mitigated vascular inflammation and permeability in endotoxemic mice, resulting in decreases in immune cell infiltration, systemic inflammation, caspase-3 activation, apoptosis, and consequent mortality. We further confirmed the inflammatory and cytotoxic effects of REDD-1 in endotoxemic REDD-1 mice. Our data support the likelihood that REDD-1 exacerbates endotoxemic inflammation via atypical NF-κB activation by sequestering IκBα.-Lee, D.-K., Kim, J.-H., Kim, J., Choi, S., Park, M., Park, W., Kim, S., Lee, K.-S., Kim, T., Jung, J., Choi, Y. K., Ha, K.-S., Won, M.-H., Billiar, T. R., Kwon, Y.-G., Kim, Y.-M. REDD-1 aggravates endotoxin-induced inflammation via atypical NF-κB activation.

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Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF‐κB pathway

Cited by 17 publications

References 48 publications

NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms

NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms

PMA/IONO affects diffuse large B-cell lymphoma cell growth through upregulation of A20 expression

REDD‐1 aggravates endotoxin‐induced inflammationVIAatypical NF‐κB activation

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