Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis.

Carter, DR; Sutton, SK; Pajic, M; Murray, J; Sekyere, EO; Fletcher, J; Beckers, A; De Preter, K; Speleman, F; George, RE; Haber, M; Norris, MD; Cheung, BB; Marshall, GM

Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis.

Carter, DR Sutton, SK Pajic, M Murray, J Sekyere, EO Fletcher, J Beckers, A De Preter, K Speleman, F George, RE Haber, M Norris, MD Cheung, BB Marshall, GM

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Publisher:: WILEY
Publication Type:: Journal Article
Citation:: Mol Oncol, 2016, 10, (6), pp. 866-878
Issue Date:: 2016-06

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Field	Value	Language
dc.contributor.author	Carter, DR
dc.contributor.author	Sutton, SK
dc.contributor.author	Pajic, M
dc.contributor.author	Murray, J
dc.contributor.author	Sekyere, EO
dc.contributor.author	Fletcher, J
dc.contributor.author	Beckers, A
dc.contributor.author	De Preter, K
dc.contributor.author	Speleman, F
dc.contributor.author	George, RE
dc.contributor.author	Haber, M
dc.contributor.author	Norris, MD
dc.contributor.author	Cheung, BB
dc.contributor.author	Marshall, GM
dc.date.accessioned	2022-08-11T02:13:28Z
dc.date.available	2016-02-19
dc.date.available	2022-08-11T02:13:28Z
dc.date.issued	2016-06
dc.identifier.citation	Mol Oncol, 2016, 10, (6), pp. 866-878
dc.identifier.issn	1574-7891
dc.identifier.issn	1878-0261
dc.identifier.uri	http://hdl.handle.net/10453/159921
dc.description.abstract	The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre-malignant sympathetic ganglia and tumors derived from the TH-MYCN mouse model of neuroblastoma, compared to non-malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN-driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre-malignant sympathetic ganglia from TH-MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN-driven neuroblastoma, and suggest that glutathione-targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	WILEY
dc.relation.ispartof	Mol Oncol
dc.relation.isbasedon	10.1016/j.molonc.2016.02.004
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Biosynthetic Pathways
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Ganglia, Sympathetic
dc.subject.mesh	Glutathione
dc.subject.mesh	Humans
dc.subject.mesh	Metabolome
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Peripheral Nervous System Neoplasms
dc.subject.mesh	Ganglia, Sympathetic
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Peripheral Nervous System Neoplasms
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Glutathione
dc.subject.mesh	Biosynthetic Pathways
dc.subject.mesh	Metabolome
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.title	Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis.
dc.type	Journal Article
utslib.citation.volume	10
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
dc.date.updated	2022-08-11T02:13:26Z
pubs.issue	6
pubs.publication-status	Published
pubs.volume	10
utslib.citation.issue	6

Abstract:

The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre-malignant sympathetic ganglia and tumors derived from the TH-MYCN mouse model of neuroblastoma, compared to non-malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN-driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre-malignant sympathetic ganglia from TH-MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN-driven neuroblastoma, and suggest that glutathione-targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease.

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http://hdl.handle.net/10453/159921