Faculty Collaboration Database

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro. BMC Cancer 2018 May 11;18(1):560

Date

05/13/2018

Pubmed ID

29751783

Pubmed Central ID

PMC5948712

DOI

10.1186/s12885-018-4474-7

Scopus ID

2-s2.0-85046622931 (requires institutional sign-in at Scopus site)   41 Citations

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.

Author List

Kunnimalaiyaan S, Schwartz VK, Jackson IA, Clark Gamblin T, Kunnimalaiyaan M

Author

Thomas Clark Gamblin MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Glycogen Synthase Kinase 3
Heterocyclic Compounds, 3-Ring
Humans
Maleimides
N-Myc Proto-Oncogene Protein
Neuroblastoma
Phosphorylation