Classical and/or alternative NF-κB pathway activation in multiple myeloma

Demchenko, Yulia N.; Glebov, O K; Zingone, Adriana; Keats, Jonathan J.; Bergsagel, P. Leif; Kuehl, W. Michael

doi:10.1182/blood-2009-09-243535

Cited by 259 publications

(254 citation statements)

References 43 publications

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“…Urban et al (2014)) studied testosterone replacement effect on NF-Binducing kinase (NIK) of old individuals and showed significant reduction levels after therapy. This protein is known to significantly be elevated in diabetic kidneys, multiple myeloma, and inflammatory arthritis (Aya et al 2005;Demchenko et al 2010;Starkey et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies

Neto

Gama

Rocha

et al. 2015

AGE

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The objective of this study was to evaluate the effects of steroid anabolic androgenic hormones use on lean mass gain in elderly men through a systematic review with a meta-analysis of randomized controlled studies. We systematically searched PubMed database until 4th October 2013. We included randomized placebo-controlled trials (RCT) that studied testosterone replacement therapy in men over 60 years of age, with total testosterone levels ≤550 ng/dl, observing gains in weight, lean mass tissue and fat mass as outcome. We excluded duplicated studies, studies which mixed men and women, and studies using weak androgens such as dehydroepiandrosterone or androstenedione. The initial search yielded 2681 articles, of which 26 were selected for full text analysis. In the end, 11 studies were included. However, 3 studies were not included in the metaanalysis. Meta-analysis showed that mean weight increased (lean mass), ranging from 1.65 (95 % CI, AGE (2015) ) kg, although it was heterogeneous (I 2 =98 %). Effect estimate was 3.59 [2.38-4.81]. Androgen therapy decreased fat mass; effect estimate was −1.78 [−2.57, −0.99] that analysis had also a high level of heterogeneity (I 2 =81 %). The results suggest that testosterone replacement therapy is able to increase muscle mass in elderly men and that is affected by the time that the treatment is carried out and the method of administration of the drug.

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Section: Discussionmentioning

confidence: 99%

Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies

Neto

Gama

Rocha

et al. 2015

AGE

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“…The transcription factor NF-B regulates apoptosis induced by genotoxic stress and is an attractive therapeutic target in tumor cells whose response to DNA-damaging agents is impaired due to compromised p53 function. Moreover, constitutive NF-B activity is a hallmark of several cancers, and mutations in NF-B pathway components have been associated with the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), breast cancer, and multiple myeloma (3,6). Thus, the inclusion of NF-B inhibitors in cancer therapy could have antioncogenic activities as well as augment the tumor chemotherapeutic response.…”

mentioning

confidence: 99%

A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage

Yang

Xia

Hermance

et al. 2011

Molecular and Cellular Biology

124

100

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In multiple tumor types, activation of the transcription factor NF-B increases the resistance of tumor cells to anticancer therapies and contributes to tumor progression. Genotoxic stress induced by chemotherapy or radiation therapy triggers the ATM-dependent translocation of NF-B essential modifier (NEMO), also designated I B kinase ␥ (IKK␥), from the nucleus to the cytosol, resulting in I B kinase activation by mechanisms not yet fully understood. RIP1 has been implicated in this response and found to be modified in cells with damaged DNA; however, the nature of the RIP1 modification and its precise role in the pathway remain unclear. Here, we show that DNA damage stimulates the formation of a cytosolic complex containing ATM, NEMO (IKK␥), RIP1, and TAK1. We find that RIP1 is modified by SUMO-1 and ubiquitin in response to DNA damage and demonstrate that modified RIP1 is required for NF-B activation and tumor cell survival. We show that ATM activates TAK1 in a manner dependent on RIP1 and NEMO. We also reveal TAK1 as a central mediator of the alternative DNA damage response pathway mediated by the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 (MAPKAP-2) kinases. These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance.The DNA damage response activates cell cycle checkpoint and survival pathways that function to prevent DNA replication until damaged DNA is repaired. These pathways include the well-characterized ATM (ataxia telangiectasia mutated)/ CHK2 and ATR (ataxia telangiectasia and Rad-3 related)/ CHK1 pathways and the more recently identified ATM/ ATR/p38 mitogen-activated protein kinase (MAPK)/MAPKactivated protein 2 (MAPKAP-2; hereinafter called MK2) checkpoint that is active in p53-deficient tumor cells (15,19). The transcription factor NF-B regulates apoptosis induced by genotoxic stress and is an attractive therapeutic target in tumor cells whose response to DNA-damaging agents is impaired due to compromised p53 function. Moreover, constitutive NF-B activity is a hallmark of several cancers, and mutations in NF-B pathway components have been associated with the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), breast cancer, and multiple myeloma (3, 6). Thus, the inclusion of NF-B inhibitors in cancer therapy could have antioncogenic activities as well as augment the tumor chemotherapeutic response.NF-B is normally held in the cytoplasm in an inactive form bound to inhibitor proteins, such as I B␣. Diverse stimuli, such as infection, proinflammatory cytokine production, or treatment with agents that induce DNA damage elicit NF-B-mediated transcriptional activity by activating the cytosolic I B kinase (IKK) complex, consisting of IKK␣ and IKK␤ and a regulatory subunit designated IKK␥ or NF-B essential modifier (NEMO) (hereinafter referred to as NEMO). IKK activation results in I B␣ phosphorylation, ubiquitination, and subsequent degradation. The NF-B (p65/p50) heterodimer is then free to en...

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“…In this context, we then examined whether hypoxia activates these 2 signaling pathways in MM cells. As shown in Figure 3, either exposure to the hypoxic mimetic lactic acid (3 mmol/L or 10 mmol/L) or hypoxia (1% O 2 ) induced a time‐dependent expression of HIF‐1α and HIF‐1β, accompanied by NF‐κB activation (reflected by upregulation of TRAF2, a key component of the NF‐κB pathway,37 and S536 phosphorylation of p65, catalyzed by activated IKK‐β 30) in H929 (Figure 3A,B), RPMI8226 (Figure 3C,D), and U266 cells (Figure S3A). However, treatment with CoCl 2 , a chemical approach widely used to mimic hypoxia, failed to induce either HIF‐1β expression or NF‐κB activation in MM cells, while resulted in HIF‐1α accumulation (Figure S3B), presumably due to blockade of its degradation 13, 38.…”

Section: Resultsmentioning

confidence: 98%

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Yang

Liu

et al. 2018

Cancer Medicine

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Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

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Classical and/or alternative NF-κB pathway activation in multiple myeloma

Cited by 259 publications

References 43 publications

Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies

Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies

A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

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