Targeting Neddylation Pathways to Inactivate Cullin-RING Ligases for Anticancer Therapy

Zhao, Yongchao; Morgan, Meredith A.; Sun, Yi

doi:10.1089/ars.2013.5795

Cited by 190 publications

(203 citation statements)

References 171 publications

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“…Previous studies demonstrated that MLN4924 inhibited the growth of a broad panel of cancer cells in vitro and in vivo (3,8,15,(29)(30)(31). On the basis of its promising anticancer efficacy and tolerated toxicity, MLN4924 has undergone preclinical or phase I clinical trials for multiple human malignancies (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Lin

Shang

et al. 2017

Oncol Lett

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Abstract. Inhibiting the protein neddylation pathway using the NEDD8-activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G 2 cell cycle arrest and enhanced the protein stability of Wee1-like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27. Furthermore, MLN4924 induced DNA damage and sensitized esophageal cancer cells to cisplatin by enhancing apoptosis. These findings extend the understanding of the function and mechanism of MLN4924 in ESCC and provide further evidence for the future development of neddylation inhibitors in clinical trials of esophageal cancer therapy, either alone or in combination.

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Section: Discussionmentioning

confidence: 99%

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Lin

Shang

et al. 2017

Oncol Lett

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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%

“…Targeting neddylation pathway has been recently demonstrated as an attractive anticancer strategy, evidenced by the efficacy of the NAE inhibitor MLN4924, a first-in-class anticancer agent, in a multitude of preclinical studies (1)(2)(3)(11)(12)(13)(14)(15)(16)(17)(18)(19). Currently, MLN4924, used as a single agent or in combination with traditional chemotherapeutics, is under investigation in quite a few of phase I/II clinical trials (http://www.clinicaltrials.gov) and has exhibited promising clinical activity in both advanced solid tumors and relapsed/refractory multiple myeloma or lymphoma (18,19).…”

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

107

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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NEDD8 ultimate buster‐1 regulates the abundance of TRF1 at telomeres by promoting its proteasomal degradation

2016

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The human telomeric protein TRF1 negatively regulates telomere length by inhibiting the access of telomerase to telomeres. Here, we describe a novel function of NEDD8 ultimate buster-1 (NUB1) for regulating the levels of TRF1 at telomeres. NUB1 is a NEDD8-interacting protein, which down-regulates the NEDD8 conjugation system. We showed that NUB1 physically interacts with TRF1 and promotes its degradation by the proteasome in the absence of NEDD8 conjugation. We also demonstrated that TRF1 is conjugated to NEDD8, and that neddylated TRF1 is targeted to the proteasome for degradation in a NUB1-dependent manner. These data suggest that NUB1 participates in telomere maintenance by regulating the levels of TRF1 at telomeres through both NEDD8-dependent and NEDD8-independent pathways.

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Targeting Neddylation Pathways to Inactivate Cullin-RING Ligases for Anticancer Therapy

Cited by 190 publications

References 171 publications

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

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

NEDD8 ultimate buster‐1 regulates the abundance of TRF1 at telomeres by promoting its proteasomal degradation

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