Serine-Glycine-One-Carbon Metabolism: The Hidden Achilles Heel of <i>MYCN</i>-Amplified Neuroblastoma?

Garcia, Aida Rodriguez; Arsenian-Henriksson, Marie

doi:10.1158/0008-5472.can-19-1816

Cited by 11 publications

(9 citation statements)

References 11 publications

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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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Section: Introductionmentioning

confidence: 99%

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

Gunda

Pathania

Chava

et al. 2020

Cancers

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“…We have recently shown that, because of MYCN-mediated metabolic reprogramming, MYCN -amplified tumor cells are increasingly dependent on key metabolic pathways for proliferation and survival, such as the serine–glycine–one-carbon metabolic network [ 9 , 10 ]. Exploiting this dependency is a promising therapeutic strategy against MYCN -amplified tumors [ 9 – 11 ]. Our current study provides further evidence in support of this strategy by identifying DHODH as a promising therapeutic target in MYCN -amplified neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…However, this metabolic reprogramming, while essential to sustain cell proliferation, renders tumor cells dependent on the SGOC pathway. As a result, MYCN -amplified neuroblastoma cells are highly sensitive to inhibitors that block this metabolic pathway, suggesting that targeting SGOC metabolism may provide selective therapeutic benefits for patients with MYCN -amplified cancers [ 10 , 11 ]. We reasoned that a comprehensive profiling of MYCN-activated metabolic pathways may identify new avenues that could be exploited therapeutically.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of both dihydroorotate dehydrogenase and nucleoside transport in MYCN-amplified neuroblastoma

Yan¹,

Ding

Zhu

et al. 2021

Cell Death Dis

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Metabolic reprogramming is an integral part of the growth-promoting program driven by the MYC family of oncogenes. However, this reprogramming also imposes metabolic dependencies that could be exploited therapeutically. Here we report that the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is an attractive therapeutic target for MYCN-amplified neuroblastoma, a childhood cancer with poor prognosis. Gene expression profiling and metabolomic analysis reveal that MYCN promotes pyrimidine nucleotide production by transcriptional upregulation of DHODH and other enzymes of the pyrimidine-synthesis pathway. Genetic and pharmacological inhibition of DHODH suppresses the proliferation and tumorigenicity of MYCN-amplified neuroblastoma cell lines. Furthermore, we obtain evidence suggesting that serum uridine is a key factor in determining the efficacy of therapeutic agents that target DHODH. In the presence of physiological concentrations of uridine, neuroblastoma cell lines are highly resistant to DHODH inhibition. This uridine-dependent resistance to DHODH inhibitors can be abrogated by dipyridamole, an FDA-approved drug that blocks nucleoside transport. Importantly, dipyridamole synergizes with DHODH inhibition to suppress neuroblastoma growth in animal models. These findings suggest that a combination of targeting DHODH and nucleoside transport is a promising strategy to overcome intrinsic resistance to DHODH-based cancer therapeutics.

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“…While numerous studies have demonstrated a key role of MYCN in NB and GBM metabolism (176)(177)(178)(179)(180), its metabolic function in medulloblastoma still remains elusive. It is likely that in these tumours, as in other cancers, MYCN reconfigures metabolism to favour aerobic glycolysis and a dependency on the serineglycine-one-carbon (SGOC) to generate metabolic products starting from serine and glycine amino acids (181).…”

Section: Future Areas Of Research For Innovative Therapies Mycn-driven Cancer Metabolismmentioning

confidence: 99%

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

et al. 2021

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The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

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Serine-Glycine-One-Carbon Metabolism: The Hidden Achilles Heel of MYCN-Amplified Neuroblastoma?

Cited by 11 publications

References 11 publications

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

Therapeutic targeting of both dihydroorotate dehydrogenase and nucleoside transport in MYCN-amplified neuroblastoma

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

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