WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells

Mackintosh, Carlos; García-Domínguez, Daniel J.; Ordóñez, José Luis; Ginel-Picardo, A.; Smith, Peter G.; Sacristán, María P.; Álava, Enrique de

doi:10.1038/onc.2012.153

Cited by 57 publications

(49 citation statements)

References 40 publications

(49 reference statements)

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“…An increasing number of studies have demonstrated that MLN4924 promotes a DNA damage response, cell cycle arrest, apoptosis and senescence in a number of cancer cell types (8,(11)(12)(13)15,22,23). In accordance with these previous studies, the current study observed that MLN4924 promotes apoptosis and the DDR in PTX-resistant NSCLC cells.…”

Section: Discussionsupporting

confidence: 79%

“…MLN4924 is a recently identified small molecule inhibitor of NAE and is currently in Phase I clinical trials (9,10). By inhibiting neddylation, MLN4924 promotes uncontrolled S-phase DNA replication as well as in the induction of DNA damage and subsequent cell death (11)(12)(13). Therefore, MLN4924 exhibits potent antitumor activity in numerous types of cancer (14).…”

Section: Introductionmentioning

confidence: 99%

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MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

Lin

et al. 2017

Oncol Lett

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Abstract. Acquired resistance to first-line chemotherapeutics, including paclitaxel (PTX), is a primary factor contributing to chemotherapy failure in non-small cell lung cancer (NSCLC) patients. Previous studies have identified that targeting NEDD8-activating enzyme (NAE) with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer. However, the underlying mechanisms are yet to be fully elucidated. The present study demonstrates that the inhibition of the neddylation pathway with MLN4924 an NAE inhibitor inhibited protein neddylation, inactivated cullin-RING E3 ligase and exhibited a potent antiproliferative effect on PTX-resistant A549 and H460 cells (A549/PTX and H460/PTX). The application of MLN4924 promotes apoptosis and DNA damage in A549/PTX and H460/PTX cells. Additionally, MLN4924 abrogated the 3-dimensional growth potential of these cells and inhibited the formation of the A549/PTX and H460/PTX spheroids. Notably, combining MLN4924 with PTX did not exhibit synergy in PTX-resistant NSCLC cells. Taken together, the results of the current study suggest that MLN4924 may be utilized as an effective strategy for the treatment of PTX-resistant NSCLC. IntroductionLung cancer is a leading cause of cancer mortality globally, in which the predominant subtype of non-small cell lung cancer (NSCLC) represents ~80% of all cases (1). Despite advances in therapy, the overall 5-year survival rate is <15% in patients with NSCLC (2). Currently, conventional chemotherapy remains an important treatment option for patients with NSCLC. Anti-mitotic agents, including docetaxel and paclitaxel (PTX), are predominantly used as chemotherapy regimens for NSCLC (3). However, taxane-based therapy is disadvantaged by the rapid emergence of acquired resistance (4). Therefore, novel therapeutic strategies that overcome the resistance to taxane-based therapy are required.Nedd8 (neural precursor cell expressed, developmentally downregulated 8), a 9-kDa small ubiquitin-like molecule, is involved in protein neddylation initiated by NEDD8 activating enzyme (NAE) (5). Nedd8 serves a role in the activation of the cullin-RING ligases (CRL), also termed SKP1-cullin-F-box (SCF) E3 ligases for its founding member (CRL/SCF) (6), which has been established to be involved in the regulation of multiple DNA replication and repair pathways (7,8). MLN4924 is a recently identified small molecule inhibitor of NAE and is currently in Phase I clinical trials (9,10). By inhibiting neddylation, MLN4924 promotes uncontrolled S-phase DNA replication as well as in the induction of DNA damage and subsequent cell death (11-13). Therefore, MLN4924 exhibits potent antitumor activity in numerous types of cancer (14). Notably, previous studies have indicated that MLN4924 overcomes platinum resistance in preclinical models of ovarian cancer (15,16), suggesting that inhibiting neddylation with MLN4924 may be a novel strategy to target drug resistance in cancer.The focus of the present study was to investigate the effects of MLN4924 on PT...

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

Lin

et al. 2017

Oncol Lett

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“…However, given the amount of CRL substrates that can be stabilized upon MLN4924 treatment, different cancer types may have distinct mechanisms of vulnerability towards MLN4924. Cytotoxic CRL substrates so far proposed in mediating MLN4924-induced cancer cell death include a cell cycle licensing factor Cdt1, NFjB inhibitor IjBa, mTOR inhibitor Deptor and REDD1 and cell cycle checkpoint proteins p21(Cip1), p27(Kip1) and WEE1 (Lin et al 2010;Swords et al 2010;Mackintosh et al 2013;Jia et al 2011a, b;Gu et al 2014). New mechanisms are emerging based on different cellular context of cancer types and here Fig.…”

Section: Cytotoxic Mechanisms Of Neddylation Inhibition In Cancer Cellsmentioning

confidence: 99%

“…The specific cell phase arrested with MLN4924 treatment also need to be evaluated on the basis of a different cellular context. Cdt1 accumulation will promote cell cycle S phase entry whereas WEE1 accumulation will trigger G2/M phase arrest (Soucy et al 2009a, b;Mackintosh et al 2013). Accumulation of cell cycle regulatory proteins upon MLN4924 treatment was constantly accompanied with DNA damage response, which was partially responsible for the apoptosis and senescence induced upon NEDDylation inhibition (Soucy et al 2009a, b;Mackintosh et al 2013;Jia et al 2011a, b).…”

Section: Skp2mentioning

confidence: 99%

“…Cdt1 accumulation will promote cell cycle S phase entry whereas WEE1 accumulation will trigger G2/M phase arrest (Soucy et al 2009a, b;Mackintosh et al 2013). Accumulation of cell cycle regulatory proteins upon MLN4924 treatment was constantly accompanied with DNA damage response, which was partially responsible for the apoptosis and senescence induced upon NEDDylation inhibition (Soucy et al 2009a, b;Mackintosh et al 2013;Jia et al 2011a, b). Given the potency and the unique mechanism of MLN4924 in inducing DNA damage in cancer cells, synergistic interactions between MLN4924 with other DNA-damage-inducing compounds (platinum, cytarabine, Cisplatin, mitomycin C) and radiation will promote its incorporation into current treatment regimens for human malignancies (Nawrocki et al 2013(Nawrocki et al , 2015Yang et al 2012;Wei et al 2012;Kee et al 2012;Jazaeri et al 2013;Garcia et al 2014).…”

Section: Skp2mentioning

confidence: 99%

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Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Shu-ju

2015

Cytotechnology

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New therapeutic intervention strategies for the treatment of human malignancies are always desired. Approval of bortezomib as a front-line treatment for multiple myeloma highlighted the significance of ubiquitin-proteasome system (UPS) as a promising therapeutic target. However, due to the broad impact of proteasome inhibition, deleterious side effects have been reported with bortezomib treatment. Cullin RING ligases (CRLs)-mediated ubiquitin conjugation process is responsible for the ubiquitin conjugation of 20 % cellular proteins that are designated for degradation through the UPS, most of them are critical proteins involved in cell cycle progression, signaling transduction and apoptosis. Studies have depicted the upstream NEDDylation pathway that controls the CRL activity by regulating the conjugation of an ubiquitin-like-protein NEDD8 to the cullin protein in the complex. A specific pharmaceutical inhibitor of NEDD8 activating enzyme (NAE; E1) MLN4924 was recently developed and has been promoted to Phase I clinical trials for the treatment of several human malignancies. This article summarizes the most recent understanding about the process of NEDD8 conjugation, its relevance for cancer therapy and molecular mechanisms responsible for the potent anti-tumor activity of MLN4924.

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Molecular Genetics of Ewing Sarcoma

Ordóñez

Amaral

Álava

2015

Encyclopedia of Life Sciences

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Ewing sarcoma (ES) is an aggressive tumour affecting mainly children and young adults. When metastases are detected, the survival rate is compromised as a result of a lack of appropriated treatments. Balanced chromosomal translocations, present in all primary ES, originate gene fusions, such as EWSR1‐FLI1, which act as aberrant transcription factors. Targeting EWSR1 ‐ FLI1 by using RNA interference approaches reduced tumour growth and tumourigenicity of ES cells in vitro and in vivo and is a good tool in order to get knowledge in the ES biology. However, possibility of taking RNA interference into clinic is limited. At present, some drugs affecting gene fusion activity have been reported to reduce tumour growth. In addition, several approaches targeting ES genetic alterations not related to gene fusions or their genetic targets have been recently reported. The use of more appropriated animal models and the study of ES tumour microenvironment and epigenetics will unveil new therapeutic targets. Key Concepts ES is an aggressive developmental tumour. Balanced chromosomal translocation and associated gene fusions are the primary molecular event in ES. Secondary molecular events in ES can define new therapeutic targets and new prognostic markers. The role played by epigenetics in ES and the regulation of chromatin remodelling is beginning to be known. Detection of ES circulating cells or identification of gene expression profiles in peripheral blood cells could become good prognostic markers. Identification of new markers of cancer stem cells could help improve ES therapy. Endoglin could be a relevant therapeutic target in ES. Osteolysis and bone remodelling are important mechanisms of ES tumour growth. ES cells secrete extracellular vesicles, containing aberrant EWSR1‐FLI1 mRNA and other growth factors, which interact with surrounding tumour cells and extracellular matrix components. Combination therapy of a dual inhibitor of IGF1R and IR pathways and a DNA damage agent can avoid resistance to IGF1R inhibitors. At present, there is a lack of appropriate genetically engineered mice (GEM) of ES.

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WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells

Cited by 57 publications

References 40 publications

MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Molecular Genetics of Ewing Sarcoma

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