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Open Access Highly Accessed Research article

The impact of S6K1 kinase on neuroblastoma cell proliferation is independent of GLI1 signaling

Yumei Diao1, Mohammed Ferdous-Ur Rahman1, Victoria E Villegas12, Malin Wickström3, John I Johnsen3 and Peter G Zaphiropoulos1*

Author Affiliations

1 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

2 Faculty of Natural Sciences and Mathematics & Doctoral Program in Biomedical Sciences Universidad del Rosario, Bogotá, Colombia

3 Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institutet, Solna, Sweden

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BMC Cancer 2014, 14:600  doi:10.1186/1471-2407-14-600

Published: 18 August 2014

Abstract

Background

The crosstalk between Hedgehog (HH) signaling and other signal transduction cascades has been extensively studied in different cancers. In neuroblastoma, mTOR/S6K1 signaling is known to have a role in the development of this disease and recent evidence also implicates the HH pathway. Moreover, S6K1 kinase has been shown to phosphorylate GLI1, the effector of HH signaling, promoting GLI1 transcriptional activity and oncogenic function in esophageal adenocarcinoma. In this study, we examined the possible interplay of S6K1 and GLI1 signaling in neuroblastoma.

Methods

siRNA knockdowns were used to suppress S6K1 and GLI1 expression, and the siRNA effects were validated by real-time PCR and Western blotting. Cell proliferation analysis was performed with the EdU incorporation assay. Cytotoxic analysis with increasing concentrations of PI3K/mTOR and GLI inhibitors, individually and in combination, was used to determine drug response.

Results

Although knockdown of either S6K1 or GLI1 reduces the cellular proliferation of neuroblastoma cells, there is little effect of S6K1 on the expression of GLI1 mRNA and protein and on the capacity of GLI1 to activate target genes. No detectable phosphorylation of GLI1 is observed prior or following S6K1 knockdown. GLI1 overexpression can not rescue the reduced proliferation elicited by S6K1 knockdown. Moreover, inhibitors of PI3K/mTOR and GLI signaling reduced neuroblastoma cell growth, but no additional growth inhibitory effects were detected when the two classes of drugs were combined.

Conclusion

Our results demonstrate that the impact of S6K1 kinase on neuroblastoma cells is not mediated through modulation of GLI1 expression/activity.

Keywords:
Hedgehog signaling; Protein phosphorylation; Signaling pathway crosstalk; Cellular proliferation; Cell growth; Oncogenic signaling; mTOR/S6K1 signaling; Signaling inhibitors