SYK Inhibition Potentiates the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells In Vitro

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 613606 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.

The Syk Kinase Promotes Mammary Epithelial Integrity and Inhibits Breast Cancer Invasion by Stabilizing the E-Cadherin/Catenin Complex

“…The signaling pathways by which Syk exerts its anti-proliferative and anti-invasive effects in epithelial cells remain unknown, and undoubtedly differ from the ones in hematopoietic cells where Syk appears to be pro-proliferative and pro-survival [29]. It is crucial to understand the mechanisms underlying this dual role because Syk kinase inhibitors might potentiate the effect of certain chemotherapeutic drugs in vitro [30] and they are being clinically evaluated but "their use might be inappropriate for people with a family history of breast cancer" [31]. Using a quantitative SILAC-based phosphoproteomic approach to compare mammary cell lines with different Syk expression or catalytic activity [32] we identified potential Syk substrate proteins involved in cell-cell adhesion (E-Cdh, α-Ctn) and epithelial polarity (occludin, Scrib, Dlg, ZO3, claudin3, InaDL, MAGUK5, and Lin7C).…”

Targeting macrophage Syk enhances responses to immune checkpoint blockade and radiotherapy in high-risk neuroblastoma

“…Immunofluorescence microscopy revealed the presence of SYK+ cells in the tissue sections of both MYCN-A and MYCN-NA NB human specimens and immunoreactivity of SYK in CD68+ TAMs ( Figure 2A ). A recent study has shown that Syk is abundantly present in both MYCN-A and MYCN-NA human NB tumors, but it is expressed explicitly in human MYCN-NA NB cell lines ( 40 ). Hence, we evaluated the protein expression of Syk in MYCN-A (SKNBE2, IMR 32) and MYCN-NA (SH-SY-5Y, SKNSH) human NB cell lines and immune cells isolated from the mice bearing NB9464 (MYCN-A) tumors.…”

“…Recent emerging studies have shown that Syk also contributes to tumorigenesis; however, its role in the progression of solid tumors is complex ( 37 – 39 ). A recent report has shown that Syk acts as a tumor promoter in neuroblastoma and Syk inhibitors potentiate the effect of chemotherapeutic drugs on NB cells in vitro ( 40 ). However, this study did not reveal the presence of Syk in immune cells and the efficacy of Syk inhibitors in suppressing NB growth in vivo .…”

Detection of Quebec Polyomavirus DNA in Samples from Different Patient Groups

“…DNA was eluted in 50 µL, and 5 µL was used in PCR. To test DNA quality, APRT PCR was carried out as previously described [ 42 ].…”