Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in Neuroblastoma

Chesler, Louis; Schlieve, Christopher R.; Goldenberg, David; Kenney, Anna Marie; Kim, Grace; McMillan, Alex; Matthay, Katherine K.; Rowitch, David H.; Weiss, William A.

doi:10.1158/0008-5472.can-05-2769

Cited by 185 publications

(205 citation statements)

References 39 publications

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“…A recent study indicated that a direct consequence of inhibiting the PI3K/Akt pathway in certain neuroblastoma cell lines is the destabilization of N-myc protein (Chesler et al, 2006). Since we found that ARC inhibits the Akt pathway in neuroblastoma cells, we decided to check if N-myc protein levels are affected.…”

Section: Targeting Akt In Neuroblastoma Cells Sk Radhakrishnan Et Almentioning

confidence: 99%

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

et al. 2007

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We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-b-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-b-Dribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARCinduced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.

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Section: Targeting Akt In Neuroblastoma Cells Sk Radhakrishnan Et Almentioning

confidence: 99%

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

et al. 2007

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“…The F1174L ALK mutation is associated preferentially with MYCN amplification in NB and induces constitutive activation of the PI3K/AKT pathway [9,10]. This constitutive activation leads to oncogenic stabilization of MYCN protein [11]. Poorly differentiated NB with high expression of MYCN and the F1174L ALK mutation define a subset of patients with high-risk NB [9,12].…”

Section: Introductionmentioning

confidence: 99%

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

et al. 2016

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“…Interestingly, in the mouse TH-MYCN neuroblastoma model it has been shown that inhibition of PI3-kinase activity destabilises MYCN protein and blocks malignant progression in neuroblastoma. 22 The regulation of the complex signalling networks involved in MYCN protein degradation is far from clear, but PI3-kinase and its downstream targets appear to have a critical role in the expression and stability of MYCN in neuroblastoma.…”

Section: Introductionmentioning

confidence: 99%

Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

et al. 2012

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Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and a disease with several different chromosomal gains and losses, which include MYCN-amplified neuroblastoma on chromosome 2, deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. Recently, activating mutations of the ALK (Anaplastic Lymphoma Kinase) RTK (Receptor Tyrosine Kinase) gene have been described in neuroblastoma. A meta-analysis of neuroblastoma cases revealed that ALK mutations (49 of 709 cases) in relation to genomic subtype were most frequently observed in MYCN amplified tumours (8.9%), correlating with a poor clinical outcome. MYCN proteins target proliferation and apoptotic pathways, and have an important role in the progression of neuroblastoma. Here, we show that both wild-type and gain-of-function mutants in ALK are able to stimulate transcription at the MYCN promoter and initiate mRNA transcription of the MYCN gene in both neuronal and neuroblastoma cell lines. Further, this stimulation of MYCN gene transcription and de novo MYCN protein expression is abrogated by specific ALK inhibitors, such as crizotinib (PF-2341066), NVP-TAE684, and by small interfering RNA to ALK resulting in a decrease in proliferation rate. Finally, co-transfection of ALK gain-of-function mutations together with MYCN leads to an increase in transformation potential. Taken together, our results indicate that ALK signalling regulates initiation of transcription of the MYCN gene providing a possible explanation for the poor clinical outcome observed when MYCN is amplified together with activated ALK.Oncogene (2012) 31, 5193 --5200; doi:10.1038/onc.2012.12; published online 30 January 2012Keywords: neuroblastoma; anaplastic lymphoma kinase; ALK; MYCN; transcription factor INTRODUCTION Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and accounts for B15% of all deaths due to paediatric tumours. 1,2 Genetically, many cases of neuroblastoma show amplification of the MYCN gene (B24% of all cases), deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. 1,3 --6 Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase (RTK) is mutated in both familial and somatic neuroblastoma. 7 --11 Moreover, these reports also indicated that downregulation or inhibition of ALK led to a marked decrease of cell proliferation, suggesting ALK as a critical factor in the initiation and progression of neuroblastoma. The ALK RTK was first described in the mid-nineties and aberrant ALK protein activity is now implicated in a range of nonhematopoietic, hematopoietic as well as neuroendocrine tumours (for a review see Palmer et al. 12 ). A recent meta-analysis of neuroblastoma has reported ALK gain-of-function mutations to be present at a frequency of 6.9% of investigated neuroblastoma tumours. Further, a comparison of the ALK mutation frequency in relation to genomic subtype revealed that ALK mutations were most frequently obs...

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Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in Neuroblastoma

Cited by 185 publications

References 39 publications

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells

Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

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