Overactivated Neddylation Pathway as a Therapeutic Target in Lung Cancer

Li, Lihui; Wang, Mingsong; Yu, Guangyang; Chen, Ping; Li, Hui; Wei, Dongping; Zhu, Ji; Xie, Li; Jia, Huixun; Shi, Jing; Li, Chunjie; Yao, Wantong; Wang, Yanchun; Gao, Qiang; Jeong, Lak Shin; Lee, Hyuk Woo; Yu, Jinha; Hu, Fengqing; Mei, Ju; Wang, Ping; Chu, Yiwei; Qi, Hui; Yang, Meng; Dong, Ziming; Sun, Yi; Hoffman, Robert M.; Jia, Lijun

doi:10.1093/jnci/dju083

Cited by 158 publications

(205 citation statements)

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“…This significant apoptotic response was attributed to the induction of c-FLIP degradation, which the authors showed to be independent of NEDD8 inhibition (67). Furthermore, it is now abundantly clear that hundereds of cellular proteins are regulated through neddylation, and consistently, pevonedistat inhibits several signal transduction pathways, including the NFkB, AKT, and the mTOR signaling pathways, in addition to cullin-signaling (28,29,(63)(64)(65)(66). Thus, pevonedistat may exhibit differential toxicities in HNSCC cells and tumors depending on the genetic backgrounds of the cells or tumors as well as on the concentrations employed.…”

Section: Discussionmentioning

confidence: 99%

“…Pevonedistat inhibits all cullin-based E3 ligases and additionally exhibits cullin-independent activity (28,29,(63)(64)(65)(66)(67). However, the results described above suggest that the radiosensitizing activity of pevonedistat is due to its ability to induce rereplication, which can be enhanced by IR.…”

Section: Induction Of Rereplication Via Cdt2 Depletion or Cdt1 Activamentioning

confidence: 98%

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The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Vanderdys

Allak

Guessous

et al. 2018

Molecular Cancer Therapeutics

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The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virusnegative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Induction Of Rereplication Via Cdt2 Depletion or Cdt1 Activamentioning

confidence: 98%

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Vanderdys

Allak

Guessous

et al. 2018

Molecular Cancer Therapeutics

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Section: Introductionmentioning

confidence: 99%

“…Neddylation is a novel type of posttranslational modification that adds the ubiquitin-like molecule NEDD8 to substrate proteins and thus regulates their function (1)(2)(3). This process is catalyzed by a cascade comprising the NEDD8-activating enzyme E1 (NAE, NAE1 and UBA3 heterodimer), NEDD8-conjugating enzyme E2, and substrate-specific NEDD8-E3 ligases (1)(2)(3). The best known substrates of neddylation are cullin family proteins, the essential subunits of multiunit Cullin-RING E3 ubiquitin ligases (CRL) whose dysfunction leads to tumorigenesis and tumor progression (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

“…This process is catalyzed by a cascade comprising the NEDD8-activating enzyme E1 (NAE, NAE1 and UBA3 heterodimer), NEDD8-conjugating enzyme E2, and substrate-specific NEDD8-E3 ligases (1)(2)(3). The best known substrates of neddylation are cullin family proteins, the essential subunits of multiunit Cullin-RING E3 ubiquitin ligases (CRL) whose dysfunction leads to tumorigenesis and tumor progression (1)(2)(3). NEDD8 conjugation also regulates the function of several other important cancer-related proteins, including oncoproteins [e.g., Mdm2 (4), HuR (5), and Smurf1 (6)] and tumor suppressors [e.g., p53 (4), pVHL (7), and TGFb type II receptor (8)].…”

Section: Introductionmentioning

confidence: 99%

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Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Chen

Liang

et al. 2016

Clinical Cancer Research

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102

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Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined.Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies.Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)-mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival.Conclusions: Our findings highlight a critical role of ATF4-CHOP-DR5 axis-mediated extrinsic apoptosis in neddylationtargeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation.

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Dysregulated NUB1 and Neddylation Enhances Rheumatoid Arthritis Fibroblast‐Like Synoviocyte Inflammatory Responses

Sendo,

Machado,

Boyle

et al. 2024

Arthritis & Rheumatology

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ObjectiveFibroblast‐like synoviocytes (FLS) contribute to the pathogenesis of rheumatoid arthritis (RA), in part due to activation of the pro‐inflammatory transcription factor NF‐κB. Neddylation is modulated by the negative regulator of ubiquitin‐like proteins‐1 (NUB1). We determined whether NUB1 and neddylation are aberrant in RA FLS thereby contributing to their aggressive phenotype.MethodsRA or osteoarthritis (OA) FLS were obtained from arthroplasty synovia. RT‐qPCR and Western blot analysis assessed gene and protein expression, respectively. NUB1 was overexpressed using an expression vector. NF‐κB activation was assessed by stimulating FLS with IL‐1β. Neddylation inhibitor (MLN4924) and proteasome inhibitor were used in migration and gene expression assays. MLN4924 was used in the K/BxN serum transfer arthritis model.ResultsEnhanced H3K27ac and H3K27me3 peaks were observed in the NUB1 promoter in OA FLS compared with RA FLS. NUB1 was constitutively expressed by FLS but induction by IL‐1β was significantly greater in OA FLS. The ratio of neddylated CUL1 to non‐neddylated CUL1 was lower in OA FLS than RA FLS. NUB1 overexpression decreased NF‐κB nuclear translocation and IL‐6 mRNA in IL‐1β‐stimulated RA FLS. MLN4924 decreased CUL1 neddylation, NF‐κB nuclear translocation and IL‐6 mRNA in IL‐1β‐stimulated RA FLS. MLN4924 significantly decreased arthritis severity in K/BxN serum‐transfer arthritis.ConclusionCUL1 neddylation and NUB1 induction is dysregulated in RA, which increases FLS activation. Inhibition of neddylation is an effective therapy in an animal model of arthritis. These data suggest that neddylation system contributes to the pathogenesis of RA and that regulation of neddylation could be a novel therapeutic approach.image

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Overactivated Neddylation Pathway as a Therapeutic Target in Lung Cancer

Abstract: Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.

Cited by 158 publications

References 44 publications

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Dysregulated NUB1 and Neddylation Enhances Rheumatoid Arthritis Fibroblast‐Like Synoviocyte Inflammatory Responses

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