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Article

Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells

  • Authors:
    • Pingping Xu
    • Lin Hou
    • Chuanxia Ju
    • Zheng Zhang
    • Wenyan Sun
    • Li Zhang
    • Jinlian Song
    • Yuqiang Lv
    • Lu Liu
    • Zhixiang Chen
    • Yanhui Wang
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong 266021, P.R. China, Department of Pharmacology, Medical College, Qingdao University, Qingdao, Shandong 266021, P.R. China, Department of Laboratory, Women and Children's Hospital of Qingdao, Qingdao, Shandong 266011, P.R. China
  • Pages: 2757-2762
    |
    Published online on: February 3, 2016
       https://doi.org/10.3892/mmr.2016.4850
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Abstract

Isatin has been shown to initiate apoptotic processes in SH‑SY5Y neuroblastoma cells. The aim of the present study was to investigate whether isatin is also able to alter the proliferation and migratory ability of SH‑SY5Y cells. The results demonstrated that the proportion of SH‑SY5Y cells in G1 phase was significantly increased following treatment with isatin for 48 h with simultaneous downregulation of cyclin D1 expression. In addition, isatin significantly inhibited cell migration and invasion, along with decreases in matrix metalloproteinase (MMP)2 and MMP9 expression. In addition, isatin reduced the levels of phosphorylated signal transducer and activator of transcription 3 (p‑STAT3) in a concentration-dependent manner. These results demonstrated that isatin induces G1‑phase arrest in SH‑SY5Y cells, possibly by decreasing cyclin D1 expression as well as inhibiting their migration and invasiveness, probably by reducing MMP2 and MMP9. These effects may be exerted by isatin via a downregulating the levels of pSTAT3.
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1 

Beierle EA, Ma X, Stewart J, Nyberg C, Trujillo A, Cance WG and Golubovskaya VM: Inhibition of focal adhesion kinase decreases tumor growth in human neuroblastoma. Cell Cycle. 9:1005–1015. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Rössler J, Monnet Y, Farace F, Opolon P, Daudigeos-Dubus E, Bourredjem A, Vassal G and Geoerger B: The selective VEGFR1-3 inhibitor axitinib (AG-013736) shows antitumor activity in human neuroblastoma xenografts. Int J Cancer. 128:2748–2758. 2011. View Article : Google Scholar

3 

Lee S, Qiao J, Paul P and Chung DH: Integrin β1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion. Surgery. 154:369–375. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Hayashi M, Okabe K, Kato K, Okumura M, Fukui R, Fukushima N and Tsujiuchi T: Differential function of lysophosphatidic acid receptors in cell proliferation and migration of neuroblastoma cells. Cancer Lett. 316:91–96. 2012. View Article : Google Scholar

6 

Gencer N, Sonmez F, Demir D, Arslan O and Kucukislamoglu M: Synthesis, structure-activity relationships and biological activity of new isatin derivatives as tyrosinase inhibitors. Curr Top Med Chem. 14:1450–1462. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Bürger S, Yafai Y, Bigl M, Wiedemann P and Schliebs R: Effect of VEGF and its receptor antagonist SU-5416, an inhibitor of angiogenesis, on processing of the β-amyloid precursor protein in primary neuronal cells derived from brain tissue of Tg2576 mice. Int J Dev Neurosci. 28:597–604. 2010. View Article : Google Scholar

8 

Lane ME, Yu B, Rice A, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG and Wadler S: A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res. 61:6170–6177. 2001.PubMed/NCBI

9 

Uchiyama H, Sowa Y, Wakada M, Yogosawa M, Nakanishi R, Horinaka M, Shimazaki C, Taniwaki M and Sakai T: Cyclin-dependent kinase inhibitor SU9516 enhances sensitivity to methotrexate in human T-cell leukemia Jurkat cells. Cancer Sci. 101:728–734. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Moshinsky DJ, Bellamacina CR, Boisvert DC, Huang P, Hui T, Jancarik J, Kim SH and Rice AG: SU9516: Biochemical analysis of cdk inhibition and crystal structure in complex with cdk2. Biochem Biophys Res Commun. 310:1026–1031. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh BK, Hubbard SR and Schlessinger J: Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science. 276:955–960. 1997. View Article : Google Scholar : PubMed/NCBI

12 

Hou L, Ju C, Zhang J, Song J, Ge Y and Yue W: Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. Eur J Pharmacol. 589:27–31. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Song J, Hou L, Ju C, Zhang J, Ge Y and Yue W: Isatin inhibits proliferation and induces apoptosis of SH-SY5Y neuroblastoma cells in vitro and in vivo. Eur J Pharmacol. 702:235–241. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Livak KJ and Schmittgen TD: Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2− ΔΔCT Method. Methods. 25:402–408. 2001. View Article : Google Scholar

15 

Baldin V, Lukas J, Marcote MJ, Pagano M and Draetta G: Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7:812–821. 1993. View Article : Google Scholar : PubMed/NCBI

16 

Lu HF, Lai KC, Hsu SC, Lin HJ, Kuo CL, Liao CL, Yang JS and Chung JG: Involvement of matrix metalloproteinases on the inhibition of cells invasion and migration by emodin in human neuroblastoma SH-SY5Y cells. Neurochem Res. 34:1575–1583. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Hodge DR, Hurt EM and Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 41:2502–2512. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Molinari M: Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 33:261–274. 2000. View Article : Google Scholar : PubMed/NCBI

19 

Sankpal UT, Abdelrahim M, Connelly SF, Lee CM, Madero-Visbal R, Colon J, Smith J, Safe S, Maliakal P and Basha R: Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro and tumor growth in orthotopic mouse model for prostate cancer. Prostate. 72:1648–1658. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Comstock CE, Revelo MP, Buncher CR and Knudsen KE: Impact of differential cyclin D1 expression and localisation in prostate cancer. Br J Cancer. 96:970–979. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Zhu S, Mott RT, Fry EA, Taneja P, Kulik G, Sui G and Inoue K: Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer. Am J Pathol. 183:1339–1350. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Zaravinos A, Lambrou GI, Volanis D, Delakas D and Spandidos DA: Spotlight on differentially expressed genes in urinary bladder cancer. PLoS One. 6:e182552011. View Article : Google Scholar : PubMed/NCBI

23 

Tsioras K, Papastefanaki F, Politis PK, Matsas R and Gaitanou M: Functional Interactions between BM88/Cend1, Ran-binding protein M and Dyrk1B kinase affect cyclin D1 levels and cell cycle progression/exit in mouse neuroblastoma cells. PLoS One. 8:e821722013. View Article : Google Scholar : PubMed/NCBI

24 

Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation and 13-cis-retinoic acid. Children's cancer group. N Engl J Med. 341:1165–1173. 1999. View Article : Google Scholar : PubMed/NCBI

25 

Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, et al: The International neuroblastoma risk group (INRG) staging system: An INRG task force report. J Clin Oncol. 27:298–303. 2009. View Article : Google Scholar :

26 

Steeg PS and Theodorescu D: Metastasis: A therapeutic target for cancer. Nat Clin Pract Oncol. 5:206–219. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Paz H, Pathak N and Yang J: Invading one step at a time: The role of invadopodia in tumor metastasis. Oncogene. 33:4193–4202. 2014. View Article : Google Scholar :

28 

Hua H, Li M, Luo T, Yin Y and Jiang Y: Matrix metalloproteinases in tumorigenesis: An evolving paradigm. Cell Mol Life Sci. 68:3853–3868. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Chaudhary AK, Singh M, Bharti AC, Asotra K, Sundaram S and Mehrotra R: Genetic polymorphisms of matrix metalloproteinases and their inhibitors in potentially malignant and malignant lesions of the head and neck. J Biomed Sci. 17:102010. View Article : Google Scholar : PubMed/NCBI

30 

DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE and Taylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res. 52:701–708. 1992.PubMed/NCBI

31 

Liu H, Jiang C, Xiong C and Ruan J: DEDC, a new flavonoid induces apoptosis via a ROS-dependent mechanism in human neuroblastoma SH-SY5Y cells. Toxicol In Vitro. 26:16–23. 2012. View Article : Google Scholar

32 

Kamran MZ, Patil P and Gude RP: Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 2013:4218212013. View Article : Google Scholar : PubMed/NCBI

33 

Walker SR, Xiang M and Frank DA: Distinct roles of STAT3 and STAT5 in the pathogenesis and targeted therapy of breast cancer. Mol Cell Endocrinol. 382:616–621. 2014. View Article : Google Scholar

34 

Overall CM and López-Otín C: Strategies for MMP inhibition in cancer: Innovations for the post-trial era. Nat Rev Cancer. 2:657–672. 2002. View Article : Google Scholar : PubMed/NCBI

35 

Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF and Hersey P: Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol. 20:416–426. 2007. View Article : Google Scholar : PubMed/NCBI

36 

Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, et al: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 10:48–54. 2004. View Article : Google Scholar : PubMed/NCBI

37 

Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli O, Schwitalla S, et al: gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 15:91–102. 2009. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Xu P, Hou L, Ju C, Zhang Z, Sun W, Zhang L, Song J, Lv Y, Liu L, Chen Z, Chen Z, et al: Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells. Mol Med Rep 13: 2757-2762, 2016.
APA
Xu, P., Hou, L., Ju, C., Zhang, Z., Sun, W., Zhang, L. ... Wang, Y. (2016). Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells. Molecular Medicine Reports, 13, 2757-2762. https://doi.org/10.3892/mmr.2016.4850
MLA
Xu, P., Hou, L., Ju, C., Zhang, Z., Sun, W., Zhang, L., Song, J., Lv, Y., Liu, L., Chen, Z., Wang, Y."Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells". Molecular Medicine Reports 13.3 (2016): 2757-2762.
Chicago
Xu, P., Hou, L., Ju, C., Zhang, Z., Sun, W., Zhang, L., Song, J., Lv, Y., Liu, L., Chen, Z., Wang, Y."Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells". Molecular Medicine Reports 13, no. 3 (2016): 2757-2762. https://doi.org/10.3892/mmr.2016.4850
Copy and paste a formatted citation
x
Spandidos Publications style
Xu P, Hou L, Ju C, Zhang Z, Sun W, Zhang L, Song J, Lv Y, Liu L, Chen Z, Chen Z, et al: Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells. Mol Med Rep 13: 2757-2762, 2016.
APA
Xu, P., Hou, L., Ju, C., Zhang, Z., Sun, W., Zhang, L. ... Wang, Y. (2016). Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells. Molecular Medicine Reports, 13, 2757-2762. https://doi.org/10.3892/mmr.2016.4850
MLA
Xu, P., Hou, L., Ju, C., Zhang, Z., Sun, W., Zhang, L., Song, J., Lv, Y., Liu, L., Chen, Z., Wang, Y."Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells". Molecular Medicine Reports 13.3 (2016): 2757-2762.
Chicago
Xu, P., Hou, L., Ju, C., Zhang, Z., Sun, W., Zhang, L., Song, J., Lv, Y., Liu, L., Chen, Z., Wang, Y."Isatin inhibits the proliferation and invasion of SH‑SY5Y neuroblastoma cells". Molecular Medicine Reports 13, no. 3 (2016): 2757-2762. https://doi.org/10.3892/mmr.2016.4850
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