MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent

Wang, Tingting; Liu, Lingling; Chen, Xuyong; Shen, Yuqing; Lian, Gaojian; Shah, Nilay; Davidoff, Andrew M.; Yang, Jun J.; Wang, Ruoning

doi:10.1038/s41419-018-0295-5

Cited by 52 publications

(60 citation statements)

References 57 publications

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“…Treatment of NB cells with rapamycin for 24 h has been shown to increase cellular levels of ROS [70], which is consistent with the increases in cellular oxidative stress in MYCN-amplified SK-N-BE(2) cells induced by ISLQ treatment for 24 h, found in our study. It is also worth noting that MYCN amplification has recently been shown to increase ROS, and to confer sensitivity to an ROS-augmenting agent in NB cells [71]. Our present study is consistent with this, as it found that ISLQ had cytotoxic effects at concentrations of 5 μM or greater, on MYCN-IMR-32 and MYCN-amplified SK-N-BE(2) cells.…”

Section: Discussionsupporting

confidence: 91%

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

et al. 2019

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Neuroblastoma (NB) is the most common extracranial solid tumor of early childhood; it accounts for approximately 8-10% of all childhood cancers and is the most common cancer in children in the first year of life. Patients in the high-risk group have a poor prognosis, with relapses being common and often refractory to drug treatment in those that survive. Moreover, the drug treatment itself can lead to a range of long-term sequelae. Therefore, there is a critical need to identify new therapeutics for NB. Isoliquiritigenin (ISLQ) is a naturally-occurring, dietary chalcone-type flavonoid with a range of biological effects that depend on the cell type and context. ISLQ has potential as an anticancer agent. Here we show that ISLQ has potent cytotoxic effects on SK-N-BE(2) and IMR-32 human NB cells, which carry amplification of the MYCN gene, the main prognostic marker of poor survival in NB. ISLQ was found to increase cellular reactive oxygen species (ROS). The cytotoxic effect of ISLQ was blocked by small molecule inhibitors of oxidative stress-induced cell death, and by the antioxidant N-acetyl-L-cysteine (NAC). Combined treatment of either SK-N-B-E(2) or IMR-32 cells with ISLQ and the anticancer agent cisplatin resulted in loss of cell viability that was greater than that induced by cisplatin alone. This study provides proof-of-principle that ISLQ is a potent cytotoxin for MYCN-amplified human NB cells. This is an important first step in rationalizing the further study of ISLQ as a potential adjunct therapy for high-risk NB.

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Section: Discussionsupporting

confidence: 91%

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

et al. 2019

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“…However, sensitivity of N-Myc high cells to inhibition of glutamine metabolism could not be rescued by external glutathione supply. Moreover, N-Myc high cells were not significantly more sensitive to the ROS-inducing agent, dimethyl fumarate, which was described to suppress neuroblastoma cell proliferation 20 . Thus, preferential killing of N-Myc high cells in the presence of glutamine metabolism inhibitors and limited glutamine supply cannot be explained by increased consumption of glutathione and increased ROS sensitivity.…”

Section: Discussionmentioning

confidence: 95%

“…By contrast, Myc-driven liver tumors rather consume glutamine by a process termed glutaminolysis, which allows for fueling into the tricarboxylic acid cycle (TCA cycle) at the level of α-ketoglutarate by activation of glutaminase, another Myc-target 19 . MYCN-driven glutaminolysis has been recently suggested as a strategy to treat Myc-driven cancers 20 . Still, tumor cell-intrinsic response patterns as a consequence of MYCN activation under varying nutrient conditions largely remain to be identified.…”

mentioning

confidence: 99%

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

Tjaden

Baum

Marquardt

et al. 2020

Sci Rep

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n-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of n-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.Myc proteins are encoded by a small family of proto-oncogenes consisting of MYC, MYCN and MYCL. In normal tissues, their expression is tightly regulated, while deregulation of MYC family members has been identified as a driving force in different cancer types. Since specific binding motifs, termed E-boxes, had been identified early on, Myc proteins were considered to be gene-specific transcription factors. This concept has been recently extended by different studies suggesting that deregulated Myc in tumors functions as a general transcriptional amplifier 1-3 . However, Myc-induced and tumor-specific mechanisms of target gene control on transcriptional level have only recently been addressed mechanistically 4 . The picture emerges that, at least in settings with vastly elevated Myc-levels, enhancer invasion by N-Myc and associated proteins contributes to tumor-specific N-Myc signatures. Moreover, the concept of Myc-mediated cell autonomous effects to boost tumor cell proliferation has been extended to include restriction of host immune reactions towards a tumor 5 . Although these efforts led to

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“…However, sensitivity of MYCN high cells to inhibition of glutamine metabolism could not be rescued by external glutathione supply. Moreover, MYCN high cells were not significantly more sensitive to the ROS-inducing agent, dimethyl fumarate, which was described to suppress neuroblastoma cell proliferation 19 . Thus, preferential killing of MYCN high cells in the presence of glutamine metabolism inhibitors and limited glutamine supply cannot be explained by increased consumption of glutathione and increased ROS sensitivity.…”

Section: Discussionmentioning

confidence: 95%

“…By contrast, MYC-driven liver tumors rather consume glutamine by a process termed glutaminolysis, which allows for fueling into the TCA cycle at the level of α-ketoglutarate by activation of glutaminase, another MYC-target 18 . MYCN-driven glutaminolysis has been recently suggested as a strategy to treat MYC-driven cancers 19 . Still, tumor cell-intrinsic response patterns as a consequence of MYCN activation under varying nutrient conditions largely remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

MYCN-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

Tjaden

Baum²,

Marquardt

et al. 2018

Preprint

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MYCN is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of MYC family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of MYC proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of MYCN overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of MYCN induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of MYCN. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of MYCN overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered MYCN induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.

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MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent

Cited by 52 publications

References 57 publications

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

MYCN-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

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