The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia

Han, Kun; Wang, Qingyang; Cao, Huanling; Qiu, Guang; Cao, Jinglin; Li, Xin; Wang, Jing; Shen, Beifen; Zhang, Jiyan

doi:10.18632/oncotarget.8068

Cited by 24 publications

(20 citation statements)

References 30 publications

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“…One well‐known inhibitor targeting NAE, MLN4924, is known to suppress cell growth by inducing p21‐dependent S and G2/M phase arrest in several cancers 54, 55, 56, 57, 58. Therefore, this study used LNM4924 to confirm neddylation of p21 (Figure 4D).…”

Section: Discussionmentioning

confidence: 97%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

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Section: Discussionmentioning

confidence: 97%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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“…A deep understanding of the principle and mechanism of these posttranslational modifications can also potentially provide new therapeutics for the cancer patients. The inhibitor of Neddylation E1 enzyme NAE-MLN4924 has been developed and displays dramatic inhibition of hematological malignancies and solid tumors [150][151][152][153][154][155][156][157][158][159][160][161]. Multiple Phase I clinical study of MLN4924 are undergoing [162][163][164][165][166].…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin and ubiquitin-like molecules in DNA double strand break repair

Qin

Lou

2020

Cell Biosci

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Both environmental and endogenous factors induce various forms of DNA damage. DNA double strand break (DSB) is the most deleterious DNA lesion. The swift initiation of a complexed network of interconnected pathways to repair the DNA lesion is essential for cell survival. In the past years, the roles of ubiquitin and ubiquitin-like proteins in DNA damage response and DNA repair has been explored. These findings help us better understand the complicated mechanism of DSB signaling pathways.

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“…Many insights into the biological function(s) of neddylation have been revealed by inhibition of NAE1 by the small molecule MLN4924, which indirectly inhibits a broad range of CRLs by blocking their neddylation [29]. Inhibition of neddylation by MLN4924 has been shown to have anti-cancer activity in vitro and in vivo, and results in the accumulation CDT1, re-replication of DNA in S-phase and G2 arrest [29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of neddylation induces mitotic defects and alters MKLP1 accumulation at the midbody during cytokinesis

2019

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The cullin-RING E3 ubiquitin ligases (CRLs) play crucial roles in modulating the stability of proteins in the cell and are, in turn, regulated by post-translational modification by the ubiquitin-like (Ubl) protein NEDD8. This process, termed neddylation, is reversible through the action of the COP9 signalosome (CSN); a multi-subunit metalloprotease conserved among eukaryotes that plays direct or indirect roles in DNA repair, cell signaling and cell cycle regulation in part through modulating the activity of the CRLs. Previously, inhibition of CRL neddylation by MLN4924, a small molecule inhibitor of the NEDD8activating enzyme 1 (NAE1), was shown to induce interphase cell cycle arrest and cell death. Using fixed and living cell microscopy, we re-evaluated the cell cycle effects of inhibition of neddylation by MLN4924 in both asynchronous and mitotic cell populations. Consistent with previous studies, treatment of asynchronous cells with MLN4924 increased CDT1 expression levels, induced G2 arrest and increased nuclear size. However, in synchronized cells treated in mitosis, mitotic defects were observed including lagging chromosomes and binucleated daughter cells. Consistent with neddylation and deneddylation playing a role in cytokinesis, NEDD8, as well as subunits of the CSN, could be localized at the midbody and cleavage furrow. Finally, treatment of mitotic cells with MLN4924 induced the premature accumulation of MKLP1 at the cleavage furrow, a key regulator of cytokinesis, which was concomitant with increased abscission delay and failure. Thus, these studies uncover an uncharacterized mitotic effect of MLN4924 on MKLP1 accumulation at the midbody and support a role for neddylation during cytokinesis.

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The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia

Cited by 24 publications

References 30 publications

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Ubiquitin and ubiquitin-like molecules in DNA double strand break repair

Inhibition of neddylation induces mitotic defects and alters MKLP1 accumulation at the midbody during cytokinesis

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