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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro

Authors: Selvi Kunnimalaiyaan, Victoriana K. Schwartz, Iris Alao Jackson, T. Clark Gamblin, Muthusamy Kunnimalaiyaan

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Neuroblastoma (NB) is a devastating disease. Despite recent advances in the treatment of NB, about 60% of high-risk NB will have relapse and therefore long-term event free survival is very minimal. We have reported that targeting glycogen synthase kinase-3 (GSK-3) may be a potential strategy to treat NB. Consequently, investigating LY2090314, a clinically relevant GSK-3 inhibitor, on NB cellular proliferation and may be beneficial for NB treatment.

Methods

The effect of LY2090314 was compared with a previously studied GSK-3 inhibitor, Tideglusib. Colorimetric, clonogenic, and live-cell image confluency assays were used to study the proliferative effect of LY2090314 on NB cell lines (NGP, SK-N-AS, and SH-SY-5Y). Western blotting and caspase glo assay were performed to determine the mechanistic function of LY2090314 in NB cell lines.

Results

LY2090314 treatment exhibited significant growth reduction starting at a 20 nM concentration in NGP, SK-N-AS, and SH-SY-5Y cells. Western blot analysis indicated that growth suppression was due to apoptosis as evidenced by an increase in pro-apoptotic markers cleaved PARP and cleaved caspase-3 and a reduction in the anti-apoptotic protein, survivin. Further, treatment significantly reduced the level of cyclin D1, a key regulatory protein of the cell cycle and apoptosis. Functionally, this was confirmed by an increase in caspase activity. LY2090314 treatment reduced the expression levels of phosphorylated GSK-3 proteins and increased the stability of β-catenin in these cells.

Conclusions

LY2090314 effectively reduces growth of both human MYCN amplified and non-amplified NB cell lines in vitro. To our knowledge, this is the first study to look at the effect of LY2090314 in NB cell lines. These results indicate that GSK-3 may be a therapeutic target for NB and provide rationale for further preclinical analysis using LY2090314.
Literature
1.
Wojtalla A, Salm F, Christiansen DG, Cremona T, Cwiek P, Shalaby T, Gross N, Grotzer MA, Arcaro A. Novel agents targeting the IGF-1R/PI3K pathway impair cell proliferation and survival in subsets of medulloblastoma and neuroblastoma. PLoS One. 2012;7(10):e47109.CrossRefPubMedPubMedCentral
2.
3.
Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, et al. The international neuroblastoma risk group (INRG) classification system: an INRG task force report. J Clin Oncol. 2009;27(2):289–97.CrossRefPubMedPubMedCentral
4.
Speleman F, Park JR, Henderson TO. Neuroblastoma: a tough nut to crack. Am Soc Clin Oncol Educ Book. 2016;35:e548–57.CrossRefPubMed
5.
Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY, Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313(18):1111–6.CrossRefPubMed
6.
7.
Charron M. Contemporary approach to diagnosis and treatment of neuroblastoma. Q J Nucl Med Mol Imaging. 2013;57(1):40–52.PubMed
8.
Naiditch JA, Jie C, Lautz TB, Yu S, Clark S, Voronov D, Chu F, Madonna MB. Mesenchymal change and drug resistance in neuroblastoma. J Surg Res. 2015;193(1):279–88.CrossRefPubMed
9.
Axelson H. The notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1. Cancer Lett. 2004;204(2):171–8.CrossRefPubMed
10.
Ayla S, Bilir A, Soner BC, Yilmaz-Dilsiz O, Erguven M, Oktem G. Notch signaling-related therapeutic strategies with novel drugs in neuroblastoma spheroids. J Pediatr Hematol Oncol. 2014;36(1):37–44.CrossRefPubMed
11.
de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM. Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem Biol Interact. 2015;242:396–406.CrossRefPubMed
12.
Ferrari-Toninelli G, Bonini SA, Uberti D, Buizza L, Bettinsoli P, Poliani PL, Facchetti F, Memo M. Targeting notch pathway induces growth inhibition and differentiation of neuroblastoma cells. Neuro-Oncology. 2010;12(12):1231–43.CrossRefPubMedPubMedCentral
13.
Pahlman S, Stockhausen MT, Fredlund E, Axelson H. Notch signaling in neuroblastoma. SeminCancer Biol. 2004;14(5):365–73.CrossRef
14.
Zage PE, Nolo R, Fang W, Stewart J, Garcia-Manero G, Zweidler-McKay PA. Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr Blood Cancer. 2012;58(5):682–9.CrossRefPubMed
15.
Domoto T, Pyko IV, Furuta T, Miyashita K, Uehara M, Shimasaki T, Nakada M, Minamoto T. Glycogen synthase kinase-3beta is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci. 2016;107(10):1363–72.CrossRefPubMedPubMedCentral
16.
McCubrey JA, Davis NM, Abrams SL, Montalto G, Cervello M, Basecke J, Libra M, Nicoletti F, Cocco L, Martelli AM, et al. Diverse roles of GSK-3: tumor promoter-tumor suppressor, target in cancer therapy. Adv Biol Regul. 2014;54:176–96.CrossRefPubMed
17.
McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL, Montalto G, D'Assoro AB, Libra M, Nicoletti F, et al. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget. 2014;5(10):2881–911.CrossRefPubMedPubMedCentral
18.
Walz A, Ugolkov A, Chandra S, Kozikowski A, Carneiro BA, O'Halloran TV, Giles FJ, Billadeau DD, Mazar AP. Molecular pathways: revisiting glycogen synthase kinase-3beta as a target for the treatment of Cancer. Clin Cancer Res. 2017;23(8):1891–7.CrossRefPubMedPubMedCentral
19.
Carter YM, Kunnimalaiyaan S, Chen H, Gamblin TC, Kunnimalaiyaan M. Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth. Cancer Biol Ther. 2014;15(5):510–5.CrossRefPubMedPubMedCentral
20.
Chen YY, Chen G, Fan Z, Luo J, Ke ZJ. GSK3beta and endoplasmic reticulum stress mediate rotenone-induced death of SK-N-MC neuroblastoma cells. Biochem Pharmacol. 2008;76(1):128–38.CrossRefPubMed
21.
Dickey A, Schleicher S, Leahy K, Hu R, Hallahan D, Thotala DK. GSK-3beta inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma neuro-2A cell line. J Neuro-Oncol. 2011;104(1):145–53.CrossRef
22.
Duffy DJ, Krstic A, Schwarzl T, Higgins DG, Kolch W. GSK3 inhibitors regulate MYCN mRNA levels and reduce neuroblastoma cell viability through multiple mechanisms, including p53 and Wnt signaling. Mol Cancer Ther. 2014;13(2):454–67.CrossRefPubMed
23.
Mathuram TL, Ravikumar V, Reece LM, Karthik S, Sasikumar CS, Cherian KM. Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G0/G1 accumulation and ROS generation. Environ Toxicol Pharmacol. 2016;46:194–205.CrossRefPubMed
24.
Gray JE, Infante JR, Brail LH, Simon GR, Cooksey JF, Jones SF, Farrington DL, Yeo A, Jackson KA, Chow KH, et al. A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Investig New Drugs. 2015;33(6):1187–96.CrossRef
25.
Kunnimalaiyaan S, Trevino J, Tsai S, Gamblin TC, Kunnimalaiyaan M. Xanthohumol-mediated suppression of Notch1 signaling is associated with antitumor activity in human pancreatic Cancer cells. Mol Cancer Ther. 2015;14(6):1395–403.CrossRefPubMedPubMedCentral
26.
Walden D, Kunnimalaiyaan S, Sokolowski K, Gamblin TC, Kunnimalaiyaan M. Antiproliferative and apoptotic effects of xanthohumol in cholangiocarcinoma. Oncotarget. 2017;8(50):88069–78.CrossRefPubMedPubMedCentral
27.
28.
Wang LL, Teshiba R, Ikegaki N, Tang XX, Naranjo A, London WB, Hogarty MD, Gastier-Foster JM, Look AT, Park JR, et al. Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children's oncology group study. Br J Cancer. 2015;113(1):57–63.CrossRefPubMedPubMedCentral
29.
Ougolkov AV, Billadeau DD. Targeting GSK-3: a promising approach for cancer therapy? FutureOncol. 2006;2(1):91–100.
30.
31.
Alao JP, Gamble SC, Stavropoulou AV, Pomeranz KM, Lam EW, Coombes RC, Vigushin DM. The cyclin D1 proto-oncogene is sequestered in the cytoplasm of mammalian cancer cell lines. Mol Cancer. 2006;5:7.CrossRefPubMedPubMedCentral
Metadata
Title
Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro
Authors
Selvi Kunnimalaiyaan
Victoriana K. Schwartz
Iris Alao Jackson
T. Clark Gamblin
Muthusamy Kunnimalaiyaan
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4474-7

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