Cell Proliferation in Neuroblastoma

Stafman, Laura L.; Beierle, Elizabeth A.

doi:10.3390/cancers8010013

Cited by 30 publications

(33 citation statements)

References 170 publications

(185 reference statements)

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“…Several transcription factors have been shown to be involved in the pathogenesis of neuroblastoma by enhancing cancer cell proliferation ( 7 ). MYCN proto-oncogene, bHLH transcription factor ( MYCN ), one of these transcription factors, is a phosphoprotein in the MYC family of transcription factors, encoded by the MYCN oncogene ( 7 ). The amplification of MYCN is one of the first most important genetic signatures of neuroblastoma ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration

et al. 2018

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Childhood neuroblastoma is one of the most common types of extra-cranial cancer affecting children with a clinical spectrum ranging from spontaneous regression to malignant and fatal progression. In order to improve the clinical outcomes of children with high-risk neuroblastoma, it is crucial to understand the tumorigenic mechanisms that govern its malignant behaviors. MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification has been implicated in the malignant, treatment-evasive nature of aggressive, high-risk neuroblastoma. In this study, we used a SILAC approach to compare the proteomic signatures of MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cells. Tumorigenic proteins, including fatty-acid binding protein 5 (FABP5), L1-cell adhesion molecule (L1-CAM), baculoviral IAP repeat containing 5 [BIRC5 (survivin)] and high mobility group protein A1 (HMGA1) were found to be significantly upregulated in the IMR-32 compared to the SK-N-SH cells and mapped to highly tumorigenic pathways including, MYC, MYCN, microtubule associated protein Tau (MAPT), E2F transcription factor 1 (E2F1), sterol regulatory element binding transcription factor 1 or 2 (SREBF1/2), hypoxia-inducible factor 1α (HIF-1α), Sp1 transcription factor (SP1) and amyloid precursor protein (APP). The transcriptional knockdown (KD) of MYCN, HMGA1, FABP5 and L1-CAM significantly abrogated the proliferation of the IMR-32 cells at 48 h post transfection. The early apoptotic rates were significantly higher in the IMR-32 cells in which FABP5 and MYCN were knocked down, whereas cellular migration was significantly abrogated with FABP5 and HMGA1 KD compared to the controls. Of note, L1-CAM, HMGA1 and FABP5 KD concomitantly downregulated MYCN protein expression and MYCN KD concomitantly downregulated L1-CAM, HMGA1 and FABP5 protein expression, while survivin protein expression was significantly downregulated by MYCN, HMGA1 and FABP5 KD. In addition, combined L1-CAM and FABP5 KD led to the concomitant downregulation of HMGA1 protein expression. On the whole, our data indicate that this inter-play between MYCN and the highly tumorigenic proteins which are upregulated in the malignant IMR-32 cells may be fueling their aggressive behavior, thereby signifying the importance of combination, multi-modality targeted therapy to eradicate this deadly childhood cancer.

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Section: Introductionmentioning

confidence: 99%

Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration

et al. 2018

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“…Neuroblastoma is an embryonal tumor of the sympathetic nervous system, arising during fetal or early postnatal life from sympathetic cells derived from the neural crest (1). In children, it is the most common extracranial solid tumor, representing approximately 7% of childhood malignancies and up to 15% of childhood cancer mortality (2). The median age of diagnosis is 22 months (3) and it rarely presents in adolescence and adulthood (4).…”

Section: Introductionmentioning

confidence: 99%

“…Management of this malignancy remains a challenge. Recently, we have witnessed a rise in the incidence of neuroblastoma with a very poor prognosis in children diagnosed after the age of 2 years, where the 5-year survival rate is only 38% (2). The heterogeneous nature of this disease makes treatment options tricky because different treatment strategies are indicated on a case by case basis, depending on the nature of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Various transcription factors have been implicated in neuroblastoma pathogenesis contributing to its uncontrolled cell proliferation, including MycN (2). The MycN phosphoprotein is a member of the MYC family of transcription factors, encoded by the MYCN oncogene (2), which drives cell proliferation. While its expression is very abundant in early embryonic development and in early neonatal life (7),…”

Section: Introductionmentioning

confidence: 99%

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L1-CAM knock-down radiosensitizes neuroblastoma IMR-32 cells by simultaneously decreasing MycN, but increasing PTEN protein expression

Rached

Nasr

Abdallah

et al. 2016

International Journal of Oncology

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Childhood neuroblastoma is one of the most malignant types of cancers leading to a high mortality rate. These cancerous cells can be highly metastatic and malignant giving rise to disease recurrence and poor prognosis. The proto-oncogene myelocytomatosis neuroblastoma (MycN) is known to be amplified in this type of cancer, thus, promoting high malignancy and resistance. The L1 cell adhesion molecule (L1-CAM) cleavage has been found upregulated in many types of malignant cancers. In the present study, we explored the interplay between L1-CAM, MycN and PTEN as well as the role played by PDGFR and VEGFR on tumorigenicity in neuroblastoma cells. We investigated the effect of L1-CAM knock-down (KD) and PDGFR/VEGFR inhibition with sunitinib malate (Sutent®) treatment on subsequent tumorsphere formation and cellular proliferation and migration in the MycN-amplified IMR-32 neuroblastoma cells. We further examined the effect of combined L1-CAM KD with Sutent treatment or radiotherapy on these cellular functions in our cells. Tumorsphere formation is one of the indicators of aggressiveness in malignant cancers, which was significantly inhibited in IMR-32 cells after L1-CAM KD or Sutent treatment, however, no synergistic effect was observed with dual treatments, rather L1-CAM KD alone showed a greater inhibition on tumorsphere formation compared to Sutent treatment alone. In addition, cellular proliferation and migration were significantly inhibited after L1-CAM KD in the IMR-32 cells with no synergistic effect observed on the rate of cell proliferation when combined with Sutent treatment. Again, L1-CAM KD alone exhibited greater inhibitory effect than Sutent treatment on cell proliferation. L1-CAM KD led to the simultaneous downregulation of MycN, but the upregulation of PTEN protein expression. Notably, radiotherapy (2 Gy) of the IMR-32 cells led to significant upregulation of both L1-CAM and MycN, which was abrogated with L1-CAM KD in our cells. In addition, L1-CAM KD radiosensitized the cells as exhibited by the synergistic effect on the reduction in cell proliferation compared to radiotherapy alone. Taken together, our data show the importance of L1-CAM interplay with MycN and PTEN on the MycN amplified neuroblastoma cell radioresistance, proliferation and motility.

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“…Due to its multiple targets, further evaluations have demonstrated the efficacy of PON in affecting other important tyrosine kinases, including EGFR, FGFR, PDGFR, and VEGFR, which are aberrantly activated in different malignancies [ 6 ]. The mechanisms of action of PON include the regulation of several intracellular signaling pathways, such as STAT3, PI3K/AKT, and ERK, which are all involved in supporting tumor cell proliferation and survival [ 7 ]. However, some studies have found an increased rate of resistance to PON in either pre-clinical or clinical settings [ 8 – 10 ], and a similar finding may therefore be possible in neuroblastoma, in which the efficacy of PON emerged from both in vitro and in vivo pre-clinical assessments [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

Corallo

Pastorino

Pantile

et al. 2020

J Exp Clin Cancer Res

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Background Despite reported advances, acquired resistance to tyrosine kinase inhibitors still represents a serious problem in successful cancer treatment. Among this class of drugs, ponatinib (PON) has been shown to have notable long-term efficacy, although its cytotoxicity might be hampered by autophagy. In this study, we examined the likelihood of PON resistance evolution in neuroblastoma and assessed the extent to which autophagy might provide survival advantages to tumor cells. Methods The effects of PON in inducing autophagy were determined both in vitro, using SK-N-BE(2), SH-SY5Y, and IMR-32 human neuroblastoma cell lines, and in vivo, using zebrafish and mouse models. Single and combined treatments with chloroquine (CQ)—a blocking agent of lysosomal metabolism and autophagic flux—and PON were conducted, and the effects on cell viability were determined using metabolic and immunohistochemical assays. The activation of the autophagic flux was analyzed through immunoblot and protein arrays, immunofluorescence, and transmission electron microscopy. Combination therapy with PON and CQ was tested in a clinically relevant neuroblastoma mouse model. Results Our results confirm that, in neuroblastoma cells and wild-type zebrafish embryos, PON induces the accumulation of autophagy vesicles—a sign of autophagy activation. Inhibition of autophagic flux by CQ restores the cytotoxic potential of PON, thus attributing to autophagy a cytoprotective nature. In mice, the use of CQ as adjuvant therapy significantly improves the anti-tumor effects obtained by PON, leading to ulterior reduction of tumor masses. Conclusions Together, these findings support the importance of autophagy monitoring in the treatment protocols that foresee PON administration, as this may predict drug resistance acquisition. The findings also establish the potential for combined use of CQ and PON, paving the way for their consideration in upcoming treatment protocols against neuroblastoma.

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Cell Proliferation in Neuroblastoma

Cited by 30 publications

References 170 publications

Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration

Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration

L1-CAM knock-down radiosensitizes neuroblastoma IMR-32 cells by simultaneously decreasing MycN, but increasing PTEN protein expression

Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

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