Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Lin,Shan; Shang,Zhaoyang; Li,Shuo; Gao,Peng; Zhang,Yi; Hou,Shuaiheng; Qin,Peng; Dong,Ziming; Hu,Tao; Chen,Ping

doi:10.3892/ol.2017.7616

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Authors:
- Shan Lin
- Zhaoyang Shang
- Shuo Li
- Peng Gao
- Yi Zhang
- Shuaiheng Hou
- Peng Qin
- Ziming Dong
- Tao Hu
- Ping Chen
View Affiliations

Affiliations: Department of Basic Science of Oncology, College of Basic Medical Sciences, Zhengzhou University, Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan 450001, P.R. China, Department of Immunotherapy, Henan Cancer Hospital and Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
Published online on: December 14, 2017 https://doi.org/10.3892/ol.2017.7616
Pages: 2583-2589

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

Inhibiting the protein neddylation pathway using the NEDD8‑activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G2 cell cycle arrest and enhanced the protein stability of Wee1‑like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27. Furthermore, MLN4924 induced DNA damage and sensitized esophageal cancer cells to cisplatin by enhancing apoptosis. These findings extend the understanding of the function and mechanism of MLN4924 in ESCC and provide further evidence for the future development of neddylation inhibitors in clinical trials of esophageal cancer therapy, either alone or in combination.

View Figures

View References

1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Yam PC, Tong D and Law S: Comparisons of sixth and seventh edition of the American Joint Cancer Committee staging systems for esophageal cancer. Ann Surg Oncol. 21:583–588. 2014. View Article : Google Scholar : PubMed/NCBI
3	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
4	Enchev RI, Schulman BA and Peter M: Protein neddylation: Beyond cullin-RING ligases. Nat Rev Mol Cell Biol. 16:30–44. 2015. View Article : Google Scholar : PubMed/NCBI
5	Abidi N and Xirodimas DP: Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic. Endocr Relat Cancer. 22:T55–T70. 2015. View Article : Google Scholar : PubMed/NCBI
6	Siergiejuk E, Scott DC, Schulman BA, Hofmann K, Kurz T and Peter M: Cullin neddylation and substrate-adaptors counteract SCF inhibition by the CAND1-like protein Lag2 in Saccharomyces cerevisiae. EMBO J. 28:3845–3856. 2009. View Article : Google Scholar : PubMed/NCBI
7	Chen P, Hu T, Liang Y, Li P, Chen X, Zhang J, Ma Y, Hao Q, Wang J, Zhang P, et al: Neddylation inhibition activates the extrinsic apoptosis pathway through ATF4-CHOP-DR5 axis in human esophageal cancer cells. Clin Cancer Res. 22:4145–4157. 2016. View Article : Google Scholar : PubMed/NCBI
8	Hua W, Li C, Yang Z, Li L, Jiang Y, Yu G, Zhu W, Liu Z, Duan S, Chu Y, et al: Suppression of glioblastoma by targeting the overactivated protein neddylation pathway. Neuro Oncol. 17:1333–1343. 2015. View Article : Google Scholar : PubMed/NCBI
9	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
10	Xie P, Zhang M, He S, Lu K, Chen Y, Xing G, Lu Y, Liu P, Li Y, Wang S, et al: The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis. Nat Commun. 5:37332014. View Article : Google Scholar : PubMed/NCBI
11	Gao Q, Yu GY, Shi JY, Li LH, Zhang WJ, Wang ZC, Yang LX, Duan M, Zhao H, Wang XY, et al: Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target. Oncotarget. 5:7820–7832. 2014. View Article : Google Scholar : PubMed/NCBI
12	Kuo KL, Ho IL, Shi CS, Wu JT, Lin WC, Tsai YC, Chang HC, Chou CT, Hsu CH, Hsieh JT, et al: MLN4924, a novel protein neddylation inhibitor, suppresses proliferation and migration of human urothelial carcinoma: In vitro and in vivo studies. Cancer Lett. 363:127–136. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wan J, Zhu J, Li G and Zhang Z: Radiosensitization of human colorectal cancer cells by MLN4924: An inhibitor of NEDD8-activating enzyme. Technol Cancer Res Treat. 15:527–534. 2016. View Article : Google Scholar : PubMed/NCBI
14	Lan H, Tang Z, Jin H and Sun Y: Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep. 6:242182016. View Article : Google Scholar : PubMed/NCBI
15	Wang Y, Luo Z, Pan Y, Wang W, Zhou X, Jeong LS, Chu Y, Liu J and Jia L: Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells. Cancer Biol Ther. 16:420–429. 2015. View Article : Google Scholar : PubMed/NCBI
16	Han K, Wang Q, Cao H, Qiu G, Cao J, Li X, Wang J, Shen B and Zhang J: The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia. Oncotarget. 7:23812–23824. 2016. View Article : Google Scholar : PubMed/NCBI
17	Bhatia S, Pavlick AC, Boasberg P, Thompson JA, Mulligan G, Pickard MD, Faessel H, Dezube BJ and Hamid O: A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma. Invest New Drugs. 34:439–449. 2016. View Article : Google Scholar : PubMed/NCBI
18	Shah JJ, Jakubowiak AJ, O'Connor OA, Orlowski RZ, Harvey RD, Smith MR, Lebovic D, Diefenbach C, Kelly K, Hua Z, et al: Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clin Cancer Res. 22:34–43. 2016. View Article : Google Scholar : PubMed/NCBI
19	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
20	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
21	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
22	Lin WC, Kuo KL, Shi CS, Wu JT, Hsieh JT, Chang HC, Liao SM, Chou CT, Chiang CK, Chiu WS, et al: MLN4924, a novel NEDD8-activating enzyme inhibitor, exhibits antitumor activity and enhances cisplatin-induced cytotoxicity in human cervical carcinoma: In vitro and in vivo study. Am J Cancer Res. 5:3350–3362. 2015.PubMed/NCBI
23	Wang X, Zhang W, Yan Z, Liang Y, Li L, Yu X, Feng Y, Fu S, Zhang Y, Zhao H, et al: Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells. Oncotarget. 7:38380–38391. 2016. View Article : Google Scholar : PubMed/NCBI
24	Ho IL, Kuo KL, Liu SH, Chang HC, Hsieh JT, Wu JT, Chiang CK, Lin WC, Tsai YC, Chou CT, et al: MLN4924 synergistically enhances cisplatin-induced cytotoxicity via JNK and Bcl-xL pathways in human urothelial carcinoma. Sci Rep. 5:169482015. View Article : Google Scholar : PubMed/NCBI
25	Chen P, Hu T, Liang Y, Li P, Chen X, Zhang J, Ma Y, Hao Q, Wang J, Zhang P, et al: Neddylation inhibition activates the extrinsic apoptosis pathway through ATF4-CHOP-DR5 axis in human esophageal cancer cells. Clin Cancer Res. 22:4145–4157. 2016. View Article : Google Scholar : PubMed/NCBI
26	Sarcar B, Kahali S, Prabhu AH, Shumway SD, Xu Y, Demuth T and Chinnaiyan P: Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol Cancer Ther. 10:2405–2414. 2011. View Article : Google Scholar : PubMed/NCBI
27	Fischle W, Tseng BS, Dormann HL, Ueberheide BM, Garcia BA, Shabanowitz J, Hunt DF, Funabiki H and Allis CD: Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature. 438:1116–1122. 2005. View Article : Google Scholar : PubMed/NCBI
28	Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, et al: Global identification of modular cullin-RING ligase substrates. Cell. 147:459–474. 2011. View Article : Google Scholar : PubMed/NCBI
29	Oladghaffari M, Islamian JP, Baradaran B and Monfared AS: MLN4924 therapy as a novel approach in cancer treatment modalities. J Chemother. 28:74–82. 2016. View Article : Google Scholar : PubMed/NCBI
30	Paiva C, Godbersen JC, Berger A, Brown JR and Danilov AV: Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents. Cell Death Dis. 6:e18072015. View Article : Google Scholar : PubMed/NCBI
31	Zhao Y, Morgan MA and Sun Y: Targeting Neddylation pathways to inactivate cullin-RING ligases for anticancer therapy. Antioxid Redox Signal. 21:2383–2400. 2014. View Article : Google Scholar : PubMed/NCBI
32	Stark GR and Taylor WR: Analyzing the G2/M checkpoint. Methods Mol Biol. 280:51–82. 2004.PubMed/NCBI
33	Florea AM and Büsselberg D: Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers. 3:1351–1371. 2011. View Article : Google Scholar : PubMed/NCBI
34	de Sousa GF, Mde A Lima, Custodio DF, Freitas VM and Monteiro G: Chemogenomic study of carboplatin in saccharomyces cerevisiae: Inhibition of the NEDDylation process overcomes cellular resistance mediated by HuR and cullin proteins. PLoS One. 10:e01453772015. View Article : Google Scholar : PubMed/NCBI
35	Pan WW, Zhou JJ, Yu C, Xu Y, Guo LJ, Zhang HY, Zhou D, Song FZ and Fan HY: Ubiquitin E3 ligase CRL4(CDT2/DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer. J Biol Chem. 288:29680–29691. 2013. View Article : Google Scholar : PubMed/NCBI