Biochemical and cellular effects of inhibiting Nedd8 conjugation

Leck, Yee Chin; Choo, Yin Yin; Tan, Chia Yee; Smith, Peter G.; Hagen, Thilo

doi:10.1016/j.bbrc.2010.06.128

Cited by 20 publications

(18 citation statements)

References 16 publications

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“…Similar anti-tumour effects of MLN4924 were observed in both in vitro and in vivo model systems of pancreatic cancer, resulting in suppression of tumour growth and metastasis (Yao et al 2014). In this system, the anti-tumourgenic effects of MLN4924 are due to the accumulation of RhoA, a member of the Rho GTPase family that is involved in the control of cellular migration (Chen et al 2009, Leck et al 2010. The assessment for the potential clinical effects of MLN4924 has so far been focussed on CRL inhibition and accumulation of CRL targets , Swords et al 2010.…”

Section: G12dmentioning

confidence: 69%

Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic

Abidi

Xirodimas

2014

Endocrine-Related Cancer

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Post-translational modification of proteins with ubiquitin and ubiquitin-like molecules (UBLs) controls a vast if not every biological process in the cell. It is not surprising that deregulation in ubiquitin and UBL signalling has been implicated in the pathogenesis of many diseases and that these pathways are considered as major targets for therapeutic intervention. In this review, we summarise recent advances in our understanding of the role of the UBL neural precursor cell expressed developmentally downregulated-8 (NEDD8) in cancer-related processes and potential strategies for the use of NEDD8 inhibitors as chemotherapeutics.

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Section: G12dmentioning

confidence: 69%

Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic

Abidi

Xirodimas

2014

Endocrine-Related Cancer

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“…The system serves as a molecular switch that regulates calcium sensitization in smooth muscle (16) and augments vasoconstriction to agonists (17). Knockdown of CUL3 or pharmacological blockade of total cullin activity increases RhoA protein expression (18,19). Similarly, interference with endogenous CUL3 by CUL3Δ9 in smooth muscle enhanced total and active RhoA expression and phosphorylated MYPT1 in S-CUL3Δ9 aortas indicative of increased ROCK signaling.…”

Section: Discussionmentioning

confidence: 99%

Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Agbor¹,

Ibeawuchi²,

Hu³

et al. 2016

JCI Insight

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“…Cullin proteins have been reported to act as core scaffolds for the assembly of cullin-RING E3 ligases (CRLs), which is the largest family of ubiquitin E3 ligases comprising several hundred members (13). The neddylation of cullins by NEDD8 results in activation of CRLs by facilitating the recruitment and positioning of ubiquitin E2 enzyme (14, 15). Therefore, the neddylation process is involved in the function of a variety of molecules by regulating their degradation through ubiquitination modification (15).…”

Section: Introductionmentioning

confidence: 99%

“…The neddylation of cullins by NEDD8 results in activation of CRLs by facilitating the recruitment and positioning of ubiquitin E2 enzyme (14, 15). Therefore, the neddylation process is involved in the function of a variety of molecules by regulating their degradation through ubiquitination modification (15). Neddylation has been demonstrated to play an essential role in cellular survival and thus is involved in diseases such as cancer (15, 16).…”

Section: Introductionmentioning

confidence: 99%

The NEDD8-Activating Enzyme Inhibitor, MLN4924, Cooperates with TRAIL to Augment Apoptosis through Facilitating c-FLIP Degradation in Head and Neck Cancer Cells

Zhao

Yue

Lonial

et al. 2011

Molecular Cancer Therapeutics

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor-selective cytokine with potential anticancer activity and is currently under clinical testing. Head and neck squamous cell carcinoma (HNSCC), like other cancer types, exhibits varied sensitivity to TRAIL. MLN4924 is a newly developed investigational small molecule inhibitor of NEDD8-activating enzyme with potent anticancer activity. This study reveals a novel function of MLN4924 in synergizing with TRAIL to induce apoptosis in HNSCC cells. MLN4924 alone effectively inhibited the growth of HNSCC cells and induced apoptosis. When combined with TRAIL, synergistic effects on decreasing the survival and inducing apoptosis of HNSCC cells occurred. MLN4924 decreased c-FLIP levels without modulating DR4 and DR5 expression. Enforced expression of c-FLIP substantially attenuated MLN4924/TRAIL-induced apoptosis. Thus c-FLIP reduction plays an important role in mediating MLN4924/TRAIL-induced apoptosis. Moreover MLN4924 decreased c-FLIP stability, increased c-FLIP ubiquitination and facilitated c-FLIP degradation, suggesting that MLN4924 decreases c-FLIP levels through promoting its degradation. MLN4924 activated JNK signaling, evidenced by increased levels of phospho-c-Jun in MLN4924-treated cells. Chemical inhibition of JNK activation not only prevented MLN4924-induced c-FLIP reduction, but also inhibited MLN4924/TRAIL-induced apoptosis, suggesting that JNK activation mediates c-FLIP downregulation and subsequent enhancement of TRAIL-induced apoptosis by MLN4924. Since knockdown of NEDD8 failed to activate JNK signaling and downregulate c-FLIP, it is likely that MLN4924 reduces c-FLIP levels and enhances TRAIL-induced apoptosis independent of NEDD8 inhibition.

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Biochemical and cellular effects of inhibiting Nedd8 conjugation

Cited by 20 publications

References 16 publications

Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic

Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic

Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

The NEDD8-Activating Enzyme Inhibitor, MLN4924, Cooperates with TRAIL to Augment Apoptosis through Facilitating c-FLIP Degradation in Head and Neck Cancer Cells

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