The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death

El-Mesery, Mohamed; Rosenthal, Tina; Rauert-Wunderlich, Hilka; Schreder, Martin; Stühmer, Thorsten; Leich, Ellen; Schlösser, Andreas; Ehrenschwender, Martin; Wajant, Harald; Siegmund, Daniela

doi:10.1038/s41419-019-1860-2

Cited by 18 publications

(21 citation statements)

References 47 publications

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“…The small molecule MLN4924 (Pevonedistat), an adenosine sulfamate analog, potently and selectively inhibits NEDD8 activating enzyme (NAE), the E1 enzyme 14 . MLN4924 inhibits several solid and liquid cancers in vitro and in vivo [14][15][16][17][18] , and Phase 1 clinical trials demonstrated good systemic tolerance and some efficacy [19][20][21] . NAE is a dimer of NAE1 and ubiquitin-like modifier activating enzyme 3 (UBA3).…”

Section: Introductionmentioning

confidence: 99%

Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

2020

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RB1 loss (RB1 null ) or MYCN amplification (MYCN amp ) in fetal human retina causes retinoblastoma. SKP2 loss kills RB1 null cells, but small molecule SKP2 inhibitors remain unexplored therapeutically. Whether SKP2 is synthetic lethal in MYCN amp retinoblastoma is unclear. SKP2 is the substrate recognition component of two Cullin-RING Ligase complexes (CRL1 SKP2 /SCF SKP2 , and CRL4 SKP2 ), a family of multiprotein E3 ubiquitin ligases. NEDD8 activating enzyme (NAE) is required for Cullin neddylation and thus CRL activation. Here, we show that the NAE inhibitor, Pevonedistat (MLN4924), potently inhibits RB1 null and MYCN amp tumors. Intravitreal MLN4924 suppressed multiple human xenografts with EC80s from 20 ng to 3.5 μg. Maximum tolerated dose (MTD) was 10-30 μg, highlighting a favorable therapeutic window. Inhibition of Cullin neddylation was similar in all cases, but cellular effects ranged from G1 arrest with apoptosis to G2/M arrest with endoreplication. However, even in less sensitive lines (EC50 ≈ 1 μM), prolonged exposure was lethal or induced persistent cytostasis. Mechanistically, depleting any single Cullin did not fully recapitulate drug phenotypes, but sensitivity to SKP2 loss correlated with that of drug. Thus, intravitreal MLN4924 is a promising new retinoblastoma therapy, mimicking the cancer-specific lethality of eliminating SKP2 complexes.

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Section: Introductionmentioning

confidence: 99%

Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

2020

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“…Our study found that TNFR1 expression is upregulated by HRG overexpression. Cellular TNFR1 level is reported to be correlated with sensitivity to MLN4924/TNF-induced cell death in multiple myeloma 43 . Increased sensitivity of HCC cells to 5-fluorouracil-induced apoptosis was found with HRG overexpression which enhanced TNFR1 protein stability in the present study, pointing out a possibility that ways to upregulate HRG expression may become an adjuvant approach for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma

et al. 2020

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Background: Tumor necrosis factor receptor 1 (TNFR1) signaling plays a pleiotropic role in the development of hepatocellular carcinoma (HCC). The formation of TNFR1-complex I supports cell survival while TNFR1-complex II leads to apoptosis, and the underlying mechanisms of the transformation of these TNFR1 complexes in HCC remain poorly defined. Methods: The interaction protein of TNFR1 was identified by GST pulldown assay, immunoprecipitation and mass spectrometry. In vitro and in vivo assay were performed to explore the biological features and mechanisms underlying the regulation of TNFR1 signals by histidine-rich glycoprotein (HRG). Data from the public databases and HCC samples were utilized to analyze the expression and clinical relevance of HRG. Results: HRG directly interacted with TNFR1 and stabilized TNFR1 protein by decreasing the Lys(K)-48 ubiquitination mediated-degradation. The formation of TNFR1-complex II was prompted by HRG overexpression via upregulating Lys(K)-63 ubiquitination of TNFR1. Besides, overexpression of HRG suppressed expression of pro-survival genes by impairing the activation of NF-κB signaling in the presence of TNFR1. Moreover, downregulation of HRG was a result of feedback inhibition of NF-κB activation in HCC. In line with the pro-apoptotic switch of TNFR1 signaling after HRG induction, overexpression of HRG inhibited cell proliferation and increased apoptosis in HCC. Conclusions: Our findings illustrate a crucial role for HRG in suppressing HCC via inclining TNFR1 to a pro-apoptotic cellular phenotype. Restoring HRG expression in HCC tissues might be a promising pharmacological approach to blocking tumor progression by shifting cellular fate from cell survival to apoptosis.

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“…Neddylation of the cullin subunit is driven by the NEDD8-activating enzyme (NAE). Blockade of neddylation can be achieved by selectively inhibiting NAE with a small molecule inhibitor MLN4924 (also known as pevonedistat) [ 24 ]. We observed that the incubation of hippocampal slices with MLN4924 prior to the induction of cLTP significantly inhibited ATF4 degradation during LTP.…”

Section: Discussionmentioning

confidence: 99%

Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity

Smith

Haynes

Hegde

2020

IJMS

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Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor activating transcription factor 4 (ATF4; also known as CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis. Using chemically induced hippocampal long-term potentiation (cLTP) as a model system, we investigate the mechanisms that control ATF4 degradation. We observed that ATF4 phosphorylated at serine-219 increases upon induction of cLTP and decreases about 30 min thereafter. Proteasome inhibitor β-lactone prevents the decrease in ATF4. We found that the phosphorylation of ATF4 is mediated by cAMP-dependent protein kinase. Our initial experiments towards the identification of the ligase that mediates ubiquitination of ATF4 revealed a possible role for β-transducin repeat containing protein (β-TrCP). Regulation of ATF4 degradation is likely to be a mechanism for determining the threshold for gene expression underlying maintenance of long-term synaptic plasticity and by extension, long-term memory.

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The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death

Cited by 18 publications

References 47 publications

Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma

Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity

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