Effect on Cell Cycle Progression by N-Myc Knockdown in SK-N-BE(2) Neuroblastoma Cell Line and Cytotoxicity with STI-571 Compound

Yu, Un-Young; Cha, Je-Eun; Ju, Sun-Young; Cho, Kyung‐Ah; Yoo, Eun-Sun; Ryu, Kyung‐Ha; Woo, So Youn

doi:10.4143/crt.2008.40.1.27

Cited by 6 publications

(5 citation statements)

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“…Early histological analyses indicated that higher KIT content in NB tumors might be associated with less aggressive tumors and a more favorable prognosis [ 42 , 43 , 44 ]. However, later studies showed a strong association of KIT with cancer stem cells, stage 4, and MYCN-amplified tumors [ 6 , 8 , 9 , 14 , 16 , 45 , 46 ], and our data strongly support these findings.…”

Section: Discussionsupporting

confidence: 89%

Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling

Lebedev

Buzdin

Khabusheva

et al. 2022

IJMS

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Neuroblastoma (NB) is a pediatric cancer with high clinical and molecular heterogeneity, and patients with high-risk tumors have limited treatment options. Receptor tyrosine kinase KIT has been identified as a potential marker of high-risk NB and a promising target for NB treatment. We investigated 19,145 tumor RNA expression and molecular pathway activation profiles for 20 cancer types and detected relatively high levels of KIT expression in NB. Increased KIT expression was associated with activation of cell survival pathways, downregulated apoptosis induction, and cell cycle checkpoint control pathways. KIT knockdown with shRNA encoded by lentiviral vectors in SH-SY5Y cells led to reduced cell proliferation and apoptosis induction up to 50%. Our data suggest that apoptosis induction was caused by mitotic catastrophe, and there was a 2-fold decrease in percentage of G2-M cell cycle phase after KIT knockdown. We found that KIT knockdown in NB cells leads to strong upregulation of other pro-survival growth factor signaling cascades such as EPO, NGF, IL-6, and IGF-1 pathways. NGF, IGF-1 and EPO were able to increase cell proliferation in KIT-depleted cells in an ERK1/2-dependent manner. Overall, we show that KIT is a promising therapeutic target in NB, although such therapy efficiency could be impeded by growth factor signaling activation.

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Section: Discussionsupporting

confidence: 89%

Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling

Lebedev

Buzdin

Khabusheva

et al. 2022

IJMS

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“…Previous reports document conflicting results on cell cycle distribution data of SK-N-BE(2) cells treated with anti- MYCN siRNAs. While Yu et al reported no apparent difference in the fraction of G1 cells after siRNA treatment, Bell et al showed that MYCN siRNA treatment increased the G1 population by 8.1% compared to a negative scrambled control siRNA [ 9 , 22 ]. In order to investigate the effect of shRNA-mediated MYCN knockdown on the cell cycle distribution pattern, we transiently transfected SK-N-BE(2) cells with plasmids expressing the aMN-887, aMN-1658 or a scrambled shRNA from a wt H1 promoter.…”

Section: Resultsmentioning

confidence: 99%

Conditional expression of retrovirally delivered anti-MYCN shRNA as an in vitro model system to study neuronal differentiation in MYCN-amplified neuroblastoma

et al. 2011

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BackgroundNeuroblastoma is a childhood cancer derived from immature cells of the sympathetic nervous system. The disease is clinically heterogeneous, ranging from neuronal differentiated benign ganglioneuromas to aggressive metastatic tumours with poor prognosis. Amplification of the MYCN oncogene is a well established poor prognostic factor found in up to 40% of high risk neuroblastomas.Using neuroblastoma cell lines to study neuronal differentiation in vitro is now well established. Several protocols, including exposure to various agents and growth factors, will differentiate neuroblastoma cell lines into neuron-like cells. These cells are characterized by a neuronal morphology with long extensively branched neurites and expression of several neurospecific markers.ResultsIn this study we use retrovirally delivered inducible short-hairpin RNA (shRNA) modules to knock down MYCN expression in MYCN-amplified (MNA) neuroblastoma cell lines. By addition of the inducer doxycycline, we show that the Kelly and SK-N-BE(2) neuroblastoma cell lines efficiently differentiate into neuron-like cells with an extensive network of neurites. These cells are further characterized by increased expression of the neuronal differentiation markers NFL and GAP43. In addition, we show that induced expression of retrovirally delivered anti-MYCN shRNA inhibits cell proliferation by increasing the fraction of MNA neuroblastoma cells in the G1 phase of the cell cycle and that the clonogenic growth potential of these cells was also dramatically reduced.ConclusionWe have developed an efficient MYCN-knockdown in vitro model system to study neuronal differentiation in MNA neuroblastomas.

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“…Consequently, cells overexpressing MYC proteins are more likely to enter S-phase with unrepaired DNA damage. In the MYCN -amplified NB cell line, SK-N-BE(2)c, knockdown of MYCN expression by siRNA can restore DNA damage induced G1 arrest [44] , indicating a causal relationship between MYCN overexpression and dysregulation of the G1 check point. In addition, both MYCN [47] and MYC [48] have been shown to directly induce DNA replication stress.…”

Section: Discussionmentioning

confidence: 98%

“…MYCN is a member of the MYC proto-oncogene family that also comprises MYC and MYCL . It has been shown that MYC proteins promote the entry of S phase [43] , [44] and inhibit G1 arrest after DNA damage [44] – [46] . Consequently, cells overexpressing MYC proteins are more likely to enter S-phase with unrepaired DNA damage.…”

Section: Discussionmentioning

confidence: 99%

A PCNA-Derived Cell Permeable Peptide Selectively Inhibits Neuroblastoma Cell Growth

Smith

et al. 2014

PLoS ONE

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Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was significantly expressed in a broad range of cancer cells and tumor tissues, but not in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interconnector domain of PCNA that is known to be a major binding site for many of PCNA's interacting proteins. We hypothesized that therapeutic agents targeting protein-protein interactions mediated through this region may confer differential toxicity to normal and malignant cells. To test this hypothesis, we designed a cell permeable peptide containing the PCNA L126-Y133 sequence. Here, we report that this peptide selectively kills human neuroblastoma cells, especially those with MYCN gene amplification, with much less toxicity to non-malignant human cells. Mechanistically, the peptide is able to block PCNA interactions in cancer cells. It interferes with DNA synthesis and homologous recombination-mediated double-stranded DNA break repair, resulting in S-phase arrest, accumulation of DNA damage, and enhanced sensitivity to cisplatin. These results demonstrate conceptually the utility of this peptide for treating neuroblastomas, particularly, the unfavorable MYCN-amplified tumors.

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Effect on Cell Cycle Progression by N-Myc Knockdown in SK-N-BE(2) Neuroblastoma Cell Line and Cytotoxicity with STI-571 Compound

Cited by 6 publications

References 10 publications

Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling

Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling

Conditional expression of retrovirally delivered anti-MYCN shRNA as an in vitro model system to study neuronal differentiation in MYCN-amplified neuroblastoma

A PCNA-Derived Cell Permeable Peptide Selectively Inhibits Neuroblastoma Cell Growth

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