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

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

SUBMITTER: Diao Y

PROVIDER: S-EPMC4152578 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Diao Yumei Y Rahman Mohammed Ferdous-Ur MF Villegas Victoria E VE Wickström Malin M Johnsen John I JI Zaphiropoulos Peter G PG

BMC cancer 20140818

<h4>Background</h4>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 ...[more]

PMID: 25134527

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Project description:BACKGROUND & AIMS:Most targeted therapies against cancer are designed to block growth factor-stimulated oncogenic growth. However, response rates are low, and resistance to therapy is high. One mechanism might relate to the ability of tumor cells to induce growth factor-independent proliferation (GFIP). This project aims to understand how (1) cancer cells preferentially derive a major growth advantage by using critical metabolic products of glucose, such as phosphoenolpyruvate (PEP), to drive proliferation and (2) esophageal squamous cell carcinoma (ESCC) cells, but not esophageal adenocarcinoma cells, can induce GFIP by using glycolysis to activate phosphohistidine (poHis)-mediated signaling through focal adhesion kinase (FAK). METHODS:The hypothesis to be tested is that ESCC GFIP induced by glucose is facilitated by PEP-mediated histidine phosphorylation (poHis) of FAK, leading to the possibility that ESCC progression can be targeted by blocking poHis signaling. Biochemical, molecular biological, and in vivo experiments including bromodeoxyuridine/5-ethynyl-2'-deoxyuridine labeling, radioisotope tracing, CRISPR gene editing, and analysis of signaling gene sets in human cancer tissues and xenograft models were performed to define the mechanisms underlying ESCC GFIP. RESULTS:Glucose promotes growth factor-independent DNA replication and accumulation of PEP in ESCC cells. PEP is the direct phospho-donor to poHis58-FAK within a known "HG" motif for histidine phosphorylation. Glucose-induced poHis58 promotes growth factor-independent FAK-mediated proliferation. Furthermore, glucose activates phosphatidylinositol-3'-kinase/AKT via poHis58-FAK signaling. Non-phosphorylatable His58A-FAK reduces xenograft growth. CONCLUSIONS:Glucose induces ESCC, but not esophageal adenocarcinoma GFIP via PEP-His58-FAK-AKT signaling. ESCC progression is controlled by actionable growth factor-independent, glucose-induced pathways that regulate proliferation through novel histidine phosphorylation of FAK.

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

Publications

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

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