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

Abstract

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...

Neural precursor cell expressed, developmentally downregulated 8 promotes tumor progression and predicts poor prognosis of patients with bladder cancer

“…For instance, MLN4924, a small molecule inhibitor of NAE, has been advanced into phase I clinical trials for certain solid tumors . MLN4924 shows antitumor activities in numerous types of cancer . In bladder cancer, MLN4924 could suppress the proliferation of tumor cells in vitro and in vivo .…”

“…24 MLN4924 shows antitumor activities in numerous types of cancer. 12,14,[25][26][27] In bladder cancer, MLN4924…”

“…Hence, inhibition of protein neddylation has become an attractive anticancer strategy . Neddylation inhibitor such as MLN4924 was found to play important roles in inhibiting tumor proliferation and metastasis . In bladder cancer, MLN4924 suppressed proliferation and migration of tumors in in vitro and in vivo experiments .…”

“…10,11 Neddylation inhibitor such as MLN4924 was found to play important roles in inhibiting tumor proliferation and metastasis. [12][13][14] In bladder cancer, MLN4924 suppressed proliferation and migration of tumors in in vitro and in vivo experiments. 15 However, the role of NEDD8 in bladder cancer remains unknown.…”

A novel strategy to block mitotic progression for targeted therapy

“…Given that activation of Cullin E3 ligase is often involved in neddylation, we ask if CP5V-induced Cdc20 degradation is sensitive to neddylation inhibitor MLN4924. To date, we treated the MDA-MB-231 cells with MLN4924, which can inactivate CRLs by inhibiting cullin neddylation [38][39][40] . As shown in Supplementary Figure 1b, we observed the treatment of MLN4924 inhibited the degradation of Cdc20 caused by CP5V.…”