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

Xu,Qiang; Lin,Guibin; Xu,Huizhe; Hu,Lulu; Wang,Yupeng; Du,Sha; Deng,Wuguo; Hu,Wenxian; Cheng,Wei; Jiang,Ke

doi:10.3892/ol.2017.7314

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

Authors:
- Qiang Xu
- Guibin Lin
- Huizhe Xu
- Lulu Hu
- Yupeng Wang
- Sha Du
- Wuguo Deng
- Wenxian Hu
- Wei Cheng
- Ke Jiang
View Affiliations

Affiliations: Department of Orthopedics, The Affiliated Yuhuangding Hospital of Qingdao University Medical College, Yantai, Shandong 264000, P.R. China, Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, Liaoning 116044, P.R. China, Key Laboratory of Biotherapy of Zhejiang Province, Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, P.R. China
Published online on: November 1, 2017 https://doi.org/10.3892/ol.2017.7314
Pages: 515-521

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Field JK and Duffy SW: Lung cancer screening: The way forward. Br J Cancer. 99:557–562. 2008. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
3	Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, Thomas S, Espinoza-Delgado I, Vokes EE, Gandara DR and Belani CP: Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol. 28:56–62. 2010. View Article : Google Scholar : PubMed/NCBI
4	Joshi M, Liu X and Belani CP: Taxanes, past, present, and future impact on non-small cell lung cancer. Anticancer Drugs. 25:571–583. 2014. View Article : Google Scholar : PubMed/NCBI
5	Xirodimas DP: Novel substrates and functions for the ubiquitin-like molecule NEDD8. Biochem Soc Trans. 36:802–806. 2008. View Article : Google Scholar : PubMed/NCBI
6	Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, et al: Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 416:703–709. 2002. View Article : Google Scholar : PubMed/NCBI
7	Jia L and Sun Y: SCF E3 ubiquitin ligases as anticancer targets. Curr Cancer Drug Targets. 11:347–356. 2011. View Article : Google Scholar : PubMed/NCBI
8	Brown JS and Jackson SP: Ubiquitylation, neddylation and the DNA damage response. Open Biol. 5:1500182015. View Article : Google Scholar : PubMed/NCBI
9	Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, Cleary JM, Mahalingam D, Pickard MD, Faessel HM, et al: Phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/mlN4924) in patients with advanced solid tumors. Clin Cancer Res. 22:847–857. 2016. View Article : Google Scholar : PubMed/NCBI
10	Nawrocki ST, Griffin P, Kelly KR and Carew JS: MLN4924: A novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy. Expert Opin Investig Drugs. 21:1563–1573. 2012. View Article : Google Scholar : PubMed/NCBI
11	Lin JJ, Milhollen MA, Smith PG, Narayanan U and Dutta A: NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res. 70:10310–10320. 2010. View Article : Google Scholar : PubMed/NCBI
12	Mackintosh C, Garcia-Dominguez DJ, Ordóñez JL, Ginel-Picardo A, Smith PG, Sacristán MP and de Álava E: WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells. Oncogene. 32:1441–1451. 2013. View Article : Google Scholar : PubMed/NCBI
13	Blank JL, Liu XJ, Cosmopoulos K, Bouck DC, Garcia K, Bernard H, Tayber O, Hather G, Liu R, Narayanan U, et al: Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. Cancer Res. 73:225–234. 2013. View Article : Google Scholar : PubMed/NCBI
14	Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, et al: An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 458:732–736. 2009. View Article : Google Scholar : PubMed/NCBI
15	Jazaeri AA, Shibata E, Park J, Bryant JL, Conaway MR, Modesitt SC, Smith PG, Milhollen MA, Berger AJ and Dutta A: Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924. Mol Cancer Ther. 12:1958–1967. 2013. View Article : Google Scholar : PubMed/NCBI
16	Nawrocki ST, Kelly KR, Smith PG, Espitia CM, Possemato A, Beausoleil SA, Milhollen M, Blakemore S, Thomas M, Berger A and Carew JS: Disrupting protein NEDDylation with MLN4924 is a novel strategy to target cisplatin resistance in ovarian cancer. Clin Cancer Res. 19:3577–3590. 2013. View Article : Google Scholar : PubMed/NCBI
17	Lv K, Liu L, Wang L, Yu J, Liu X, Cheng Y, Dong M, Teng R, Wu L, Fu P, et al: Lin28 mediates paclitaxel resistance by modulating p21, Rb and Let-7a miRNA in breast cancer cells. PLoS One. 7:e400082012. View Article : Google Scholar : PubMed/NCBI
18	Kim EH, Min HY, Chung HJ, Song J, Park HJ, Kim S and Lee SK: Anti-proliferative activity and suppression of P-glycoprotein by (−)-antofine, a natural phenanthroindolizidine alkaloid, in paclitaxel-resistant human lung cancer cells. Food Chem Toxicol. 50:1060–1065. 2012. View Article : Google Scholar : PubMed/NCBI
19	Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, et al: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 370:332–344. 2016. View Article : Google Scholar : PubMed/NCBI
20	Hu L, Sun S, Wang T, Li Y, Jiang K, Lin G, Ma Y, Barr MP, Song F, Zhang G and Meng S: Oncolytic newcastle disease virus triggers cell death of lung cancer spheroids and is enhanced by pharmacological inhibition of autophagy. Am J Cancer Res. 5:3612–3623. 2015.PubMed/NCBI
21	Li H, Tan M, Jia L, Wei D, Zhao Y, Chen G, Xu J, Zhao L, Thomas D, Beer DG and Sun Y: Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis. J Clin Invest. 124:835–846. 2014. View Article : Google Scholar : PubMed/NCBI
22	Li L, Wang M, Yu G, Chen P, Li H, Wei D, Zhu J, Xie L, Jia H, Shi J, et al: Overactivated neddylation pathway as a therapeutic target in lung cancer. J Natl Cancer Inst. 106:dju0832014. View Article : Google Scholar : PubMed/NCBI
23	Luo Z, Yu G, Lee HW, Li L, Wang L, Yang D, Pan Y, Ding C, Qian J, Wu L, et al: The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth. Cancer Res. 72:3360–3371. 2012. View Article : Google Scholar : PubMed/NCBI
24	Gu Y, Kaufman JL, Bernal L, Torre C, Matulis SM, Harvey RD, Chen J, Sun SY, Boise LH and Lonial S: MLN4924, an NAE inhibitor, suppresses AKT and mTOR signaling via upregulation of REDD1 in human myeloma cells. Blood. 123:3269–3276. 2014. View Article : Google Scholar : PubMed/NCBI
25	Loessner D, Flegg JA, Byrne HM, Clements JA and Hutmacher DW: Growth of confined cancer spheroids: A combined experimental and mathematical modelling approach. Integr Biol (Camb). 5:597–605. 2013. View Article : Google Scholar : PubMed/NCBI
26	Pampaloni F, Reynaud EG and Stelzer EH: The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol. 8:839–845. 2007. View Article : Google Scholar : PubMed/NCBI