Targeting metabolic activity in high-risk neuroblastoma through Monocarboxylate Transporter 1 (MCT1) inhibition

Khan, Aaminah; Valli, Emanuele; Lam, Hayley; Scott, David A.; Murray, Jayne; Hanssen, Kimberley M.; Eden, Georgina; Gamble, Laura D.; Pandher, Ruby; Flemming, Claudia L.; Allan, Sophie; Osterman, Andrei L.; Haber, Michelle; Norris, Murray D.; Fletcher, Jamie I.; Yu, Denise

doi:10.1038/s41388-020-1235-2

Cited by 30 publications

(25 citation statements)

References 51 publications

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“…However, given the small numbers of possible target genes, no pathway or process was statistically over-represented. Nonetheless, it should be noted that clear-cell renal cell carcinoma is especially characterized by impaired cellular metabolism and metabolic reprogramming characterized by increased glycolysis and lactate production, and abnormal accumulations of lipids and reduced oxidative phosphorylation [49,50]. ZNF433 may be involved in cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

The Identification of Zinc-Finger Protein 433 as a Possible Prognostic Biomarker for Clear-Cell Renal Cell Carcinoma

et al. 2021

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Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of all urological cancers, with poor prognosis and high mortality. At late stages, ccRCC is known to be mainly resistant to chemotherapy and radiotherapy. Therefore, it is urgent and necessary to identify biomarkers that can facilitate the early detection of ccRCC in patients. In this study, the levels of transcripts of ccRCC from The Cancer Genome Atlas (TCGA) dataset were used to identify prognostic biomarkers in this disease. Analyzing the data obtained indicated that the KRAB-ZNF protein is significantly suppressed in clear-cell carcinomas. Furthermore, ZNF433 is differentially expressed in ccRCC in a stage- and histological-grade-specific manner. In addition, ZNF433 expression was correlated with metastasis, with greater node involvement associated with lower ZNF433 expression (p < 0.01) and with a more unsatisfactory overall survival outcome (HR, 0.45; 95% CI, 0.33–0.6; p = 8.5 × 10−8). Since ccRCC is characterized by mutations in proteins that alter epigenetic modifications and /or chromatin remodeling, we examined the expression of ZNF433 transcripts in ccRCC with wildtype and mutated forms of BAP1, KDMC5, MTOR, PBRM1, SETD2, and VHL. Analysis revealed that ZNF433 expression was significantly reduced in ccRCC with mutations in the BAP1, SETD2, and KDM5C genes (p < 0.05). In addition, the ZNF433 promoter region was highly methylated, and hypermethylation was significantly associated with mRNA suppression (p < 2.2 × 10−16). In silico analysis of potential ZNF target genes found that the largest group of target genes are involved in cellular metabolic processes, which incidentally are particularly impaired in ccRCC. It was concluded from this study that gene expression of ZNF433 is associated with cancer progression and poorer prognosis, and that ZNF433 behaves in a manner that suggests that it is a prognostic marker and a possible tumor-suppressor gene in clear-cell renal cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

The Identification of Zinc-Finger Protein 433 as a Possible Prognostic Biomarker for Clear-Cell Renal Cell Carcinoma

et al. 2021

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“…As a result, MCT1 targeting is believed to be effective in NB therapy. It is even revealed that co‐inhibition of MCT1 and lactate dehydrogenase A (the enzyme that regulates lactate production) causes a synergistic effect in NB therapy, even in resistant tumors (Fang et al, 2006; Khan et al, 2020).…”

Section: Targets For Drug Delivery To Nbmentioning

confidence: 99%

Neuroblastoma‐targeted nanoparticles and novel nanotechnology‐based treatment methods

Mobasheri

Rayzan

Shabani

et al. 2020

Journal Cellular Physiology

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Neuroblastoma is a complicated pediatric tumor, originating from the neural crest, which is the most prevalent in adrenal glands, but may rarely be seen in some other tissues as well. Studies are focused on developing new strategies through novel chemo-and immuno-therapeutic drug targets. Different types of oncogenes such as MYCN, tumor suppressor genes such as p53, and some structural genes such as vascular endothelial growth factor are considered as targets for neuroblastoma therapy. The individual expression patterns in NB cells make them appropriate for this purpose. The combined effect of nano-drug delivery systems and specific drug targets will result in lower systemic side effects, prolonged therapeutic effects, and improvements in the pharmacokinetic properties of the drugs. Some of these novel drug delivery systems with a focus on liposomes as carriers are also discussed. In this review, genes and protein products that are beneficial as drug targets in the treatment of neuroblastoma have been discussed.

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“…5 Importantly, the MYCN oncogene is amplified in 25% of primary neuroblastoma and has been demonstrated to activate the lactate transporter monocarboxylate transporter 1 (MCT1). 6 Interestingly, Johnston et. al observed 13 C-labeled lactate from the blood in tumors of all seven neuroblastoma patients, something that would not be detected in conventional in vitro models, suggesting that lactate uptake, possibly via MCT1, is a common feature.…”

mentioning

confidence: 99%

“…3 Lactate uptake has been associated with poor overall survival as some cancers use lactate as fuel. 6 These findings can therefore have important clinical consequences. Several small molecules (e.g., Phloretin, WZB117, Fasentin) targeting glucose transporters (GLUTs), which prevent cellular glucose entry, showed promising results in preclinical models of various cancer types.…”

mentioning

confidence: 99%

A powerful tool to study metabolic reprogramming in pediatric cancers

Missiaen

Simon

2021

Med

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Targeting metabolic activity in high-risk neuroblastoma through Monocarboxylate Transporter 1 (MCT1) inhibition

Cited by 30 publications

References 51 publications

The Identification of Zinc-Finger Protein 433 as a Possible Prognostic Biomarker for Clear-Cell Renal Cell Carcinoma

The Identification of Zinc-Finger Protein 433 as a Possible Prognostic Biomarker for Clear-Cell Renal Cell Carcinoma

Neuroblastoma‐targeted nanoparticles and novel nanotechnology‐based treatment methods

A powerful tool to study metabolic reprogramming in pediatric cancers

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