Abstract
Neuroblastoma is a malignancy arising from the developing sympathetic nervous system and the most common and deadly cancer of infancy. New therapies are needed to improve the prognosis for high-risk patients and to reduce toxicity and late effects. Spleen tyrosine kinase (SYK) has previously been identified as a promising drug target in various inflammatory diseases and cancers but has so far not been extensively studied as a potential therapeutic target in neuroblastoma. In this study, we observed elevated SYK gene expression in neuroblastoma compared to neural crest and benign neurofibroma. While SYK protein was detected in the majority of examined neuroblastoma tissues it was less frequently observed in neuroblastoma cell lines. Depletion of SYK by siRNA and the use of small molecule SYK inhibitors significantly reduced the cell viability of neuroblastoma cell lines expressing SYK protein. Moreover, SYK inhibition decreased ERK1/2 and Akt phosphorylation. The SYK inhibitor BAY 61-3606 enhanced the effect of different chemotherapeutic drugs. Transient expression of a constitutive active SYK variant increased the viability of neuroblastoma cells independent of endogenous SYK levels. Collectively, our findings suggest that targeting SYK in combination with conventional chemotherapy should be further evaluated as a treatment option in neuroblastoma.
Highlights
Tyrosine kinases are important mediators of cellular functions such as proliferation, differentiation, metabolism, and survival
72 kDa non-receptor tyrosine kinase consisting of two SRC homology 2 (SH2) domains and a kinase domain joined by two linker regions, interdomains A and B [4]
We examined Spleen tyrosine kinase (SYK) gene expression using the publicly available R2: Genomics analysis and visualization platform and observed that SYK expression was higher in four different neuroblastoma cohorts compared to neural crest cells and benign neurofibroma (Figure 1A)
Summary
Tyrosine kinases are important mediators of cellular functions such as proliferation, differentiation, metabolism, and survival. It mediates inflammatory responses by linking immune cell receptors to various intracellular signaling networks and exhibits, for example, a pivotal role in B-cell development [4,8,9]. SYK promotes, in concert with PKCδ, the expression of anti-apoptotic Mcl-1 in B-cell chronic lymphocytic leukemia (CLL) [10] and regulates actin filament assembly and dynamics through phosphorylation of cortactin and cofilin in ovarian cancer, thereby promoting migration and invasion [11]. Phosphorylated SYK has been observed in specific cell types and areas of the developing nervous system and diverse functions have been described [12,13,14]
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