Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer

Nawrocki, Steffan T.; Kelly, Kevin R.; Smith, Peter G.; Espitia, Claudia M.; Possemato, Anthony; Beausoleil, Sean A.; Milhollen, Michael A.; Blakemore, Stephen J.; Thomas, Michael; Berger, Allison; Carew, Jennifer S.

doi:10.1158/1078-0432.ccr-12-3212

Cited by 94 publications

(101 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). These studies highlighted potential incorporation of MLN4924 into current treatment regimens as addition of MLN4924 was shown to sensitize malignant cells to those traditional therapeutic strategies.…”

Section: Skp2mentioning

confidence: 99%

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

Shu-ju

2015

Cytotechnology

View full text Add to dashboard Cite

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.

show abstract

Section: Skp2mentioning

confidence: 99%

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

Shu-ju

2015

Cytotechnology

View full text Add to dashboard Cite

show abstract

“…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%

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

108

102

View full text Add to dashboard Cite

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.

show abstract

“…Previous studies have established that targeting NAE with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer (15,16). Additionally, a synergic cytotoxic effect between cisplatin and MLN4924 was observed in platinum-sensitive and -resistant ovarian cancer cells (15,16).…”

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

“…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 PTX-resistant NSCLC cells. The results identified that MLN4924 suppresses the growth of PTX-resistant NSCLC cells by inducing apoptosis and DNA damage.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Lin

et al. 2017

Oncol Lett

View full text Add to dashboard Cite

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...

show abstract

Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer

Cited by 94 publications

References 41 publications

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

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

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

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

Contact Info

Product

Resources

About