Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

Procházka, Pavel; Hraběta, Jan; Vícha, Aleš; Cipro, Simon; Stejskalová, Eva; Musil, Zdeněk; Vodička, Pavel; Eckschlager, Tomáš

doi:10.3892/or.2013.2383

Cited by 9 publications

(3 citation statements)

References 37 publications

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“…We revalidated the marked phenotypical alterations in UKF-NB-4 CDDP cells compared to the parental cells [22,31]. Figure 1A illustrates that induction of CDDP chemoresistance results in pronounced morphological changes from initial polygonal morphology of UKF-NB-4 cells to more globular and less-elongated UKF-NB-4 CDDP cells.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells

Rodrigo

Buchtelová

Jiménez

et al. 2019

Cells

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The efficiency of cisplatin (CDDP) is significantly hindered by the development of resistance during the treatment course. To gain a detailed understanding of the molecular mechanisms underlying the development of cisplatin resistance, we comparatively analyzed established a CDDP-resistant neuroblastoma cell line (UKF-NB-4CDDP) and its susceptible parental cells (UKF-NB-4). We verified increased chemoresistance of UKF-NB-4CDDP cells by analyzing the viability, induction of apoptosis and clonal efficiency. To shed more light on this phenomenon, we employed custom cDNA microarray (containing 2234 probes) to perform parallel transcriptomic profiling of RNA and identified that 139 genes were significantly up-regulated due to CDDP chemoresistance. The analyses of molecular pathways indicated that the top up-regulation scoring functions were response to stress, abiotic stimulus, regulation of metabolic process, apoptotic processes, regulation of cell proliferation, DNA repair or regulation of catalytic activity, which was also evidenced by analysis of molecular functions revealing up-regulation of genes encoding several proteins with a wide-spectrum of enzymatic activities. Functional analysis using lysosomotropic agents chloroquine and bafilomycin A1 validated their potential to re-sensitize UKF-NB-4CDDP cells to CDDP. Taken together, the identification of alterations in specific genes and pathways that contribute to CDDP chemoresistance may potentially lead to a renewed interest in the development of novel rational therapeutics and prognostic biomarkers for the management of CDDP-resistant neuroblastoma.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells

Rodrigo

Buchtelová

Jiménez

et al. 2019

Cells

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“…The apoptotic control mechanism proposed in the present study for MYCN -amplified neuroblastoma cells via c- myb and E2F1 -associated MYCN overexpression can explain why the MYCN gene copy number increases despite reductions in mRNA expression levels of MYCN following c- myb RNAi treatment. In cisplatin-resistant UKF-NB-4 neuroblastoma cells with MYCN amplification, MYCN expression levels increased although no significant change was observed in the MYCN copy number following cisplatin treatment, suggesting that alterations in MYCN expression may not always be associated with variations in MYCN copy number (66). MYCN expression may be controlled by mechanisms independent from MYCN copy number under discrete conditions in neuroblastoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

MYCN is amplified during S phase, and c‑myb is involved in controlling MYCN expression and amplification in MYCN‑amplified neuroblastoma cell lines

Aygün

Altungoz

2018

Mol Med Report

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Neuroblastoma derived from primitive sympathetic neural precursors is a common type of solid tumor in infants. MYCN proto-oncogene bHLH transcription factor (MYCN) amplification and 1p36 deletion are important factors associated with the poor prognosis of neuroblastoma. Expression levels of MYCN and c-MYB proto-oncogene transcription factor (c-myb) decline during the differentiation of neuroblastoma cells; E2F transcription factor 1 (E2F1) activates the MYCN promoter. However, the underlying mechanism of MYCN overexpression and amplification requires further investigation. In the present study, potential c-Myb target genes, and the effect of c-myb RNA interference (RNAi) on MYCN expression and amplification were investigated in MYCN-amplified neuroblastoma cell lines. The mRNA expression levels and MYCN gene copy number in five neuroblastoma cell lines were determined by quantitative polymerase chain reaction. In addition, variations in potential target gene expression and MYCN gene copy number between pre- and post-c-myb RNAi treatment groups in MYCN-amplified Kelly, IMR32, SIMA and MHH-NB-11 cell lines, normalized to those of non-MYCN-amplified SH-SY5Y, were examined. To determine the associations between gene expression levels and chromosomal aberrations, MYCN amplification and 1p36 alterations in interphases/metaphases were analyzed using fluorescence in situ hybridization. Statistical analyses revealed correlations between 1p36 alterations and the expression of c-myb, MYB proto-oncogene like 2 (B-myb) and cyclin dependent kinase inhibitor 1A (p21). Additionally, the results of the present study also demonstrated that c-myb may be associated with E2F1 and L3MBTL1 histone methyl-lysine binding protein (L3MBTL1) expression, and that E2F1 may contribute to MYCN, B-myb, p21 and chromatin licensing and DNA replication factor 1 (hCdt1) expression, but to the repression of geminin (GMNN). On c-myb RNAi treatment, L3MBTL1 expression was silenced, while GMNN was upregulated, indicating G2/M arrest. In addition, MYCN gene copy number increased following treatment with c-myb RNAi. Notably, the present study also reported a 43.545% sequence identity between upstream of MYCN and Drosophila melanogaster amplification control element 3, suggesting that expression and/or amplification mechanisms of developmentally-regulated genes may be evolutionarily conserved. In conclusion, c-myb may be associated with regulating MYCN expression and amplification. c-myb, B-myb and p21 may also serve a role against chromosome 1p aberrations. Together, it was concluded that MYCN gene is amplified during S phase, potentially via a replication-based mechanism.

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“…Multiple mechanisms mediated by oncogenes, such as exosomal-microRNAs and cell signaling pathways, were identified to promote CDDP-insensitivity in neuroblastoma [ 10 , 18 , 19 , 20 ]. The oncogenes, including v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) and Hypoxia-inducible factor (HIF)-1∝, were shown to regulate metabolism and mediate CDDP-resistance in neuroblastoma [ 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

Gunda

Pathania

Chava

et al. 2020

Cancers

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Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas.

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Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

Cited by 9 publications

References 37 publications

Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells

Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells

MYCN is amplified during S phase, and c‑myb is involved in controlling MYCN expression and amplification in MYCN‑amplified neuroblastoma cell lines

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

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