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Combined Dietary and Pharmacological Depletion of Polyamines Targets Oncogenic Translation in Neuroblastoma

ABSTRACT: Cancer growth is fueled by nutrients obtained from circulation and local biosynthesis. Isolating and exploiting tumoral nutrient dependencies to potentiate current anti-cancer therapies is undergoing active research. We used unbiased metabolomics on patient samples and identified reprogramming of the arginine-proline-glutamine axis in MYCN amplified neuroblastoma. Tumoral acquisition of these non-essential amnio acids, as revealed by stable isotope tracing, was primarily by import, while extra-tumoral deamination of arginine indirectly feeds tumor ornithine via circulation. Dietary depletion of proline and arginine reduced systemic ornithine, the direct precursor of polyamine biosynthesis, and in combination with the clinically approved polyamine biosynthesis inhibitor, difluoromethylornithine, enhanced their depletion to improve survival in a MYCN-driven neuroblastoma mouse model. Mechanistically, ribosome profiling indicated specific translation defects, with ribosomal pausing at adenine-ending codons, to cause reprogramed protein biosynthesis affecting cell cycle and inducing neuronal differentiation. This work provides proof of concept for combined small molecule and nutrient depletion therapy for simultaneous targeting of translation in cancers dependent on external nutrient uptake.

ORGANISM(S): Mus musculus

PROVIDER: GSE244378 | GEO | 2024/02/09

REPOSITORIES: GEO

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Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDA) cells have a distinct dependence on de novo ornithine synthesis from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor growth. This directional OAT activity is normally largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginase (ARG) to generate arginine-derived ornithine, the substrate for polyamine synthesis. This dependence associates with arginine depletion in PDA tumor microenvironment, and is driven by mutant KRAS, which induces the expression of OAT and polyamine synthesis enzymes, including the rate-limiting enzyme ornithine decarboxylase-1 (ODC1). Loss of OAT, but not ARG2, largely mimics loss of ODC1, altering the transcriptional profiles in PDA cells, which in turn correlate with alterations in open chromatin states.

2023-01-01 | GSE193411 | GEO

The effect of DFMO on the gene expression in pro-inflammatory cytokine-treated human islets

Project description:Inhibition of polyamine biosynthesis using α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), reduces β-cell stress and type 1 diabetes (T1D) incidence in preclinical models. However, underlying cellular and molecular mechanisms and the tolerability and effectiveness of polyamine depletion by DFMO in humans with T1D remain unknown. Transcriptomics and proteomics of cytokine-stressed human islets treated with DFMO reveal alterations in mRNA translation, nascent protein transport, and secretion. Collectively, our data suggest that inhibition of polyamine biosynthesis may preserve β-cell function in T1D via islet cell-autonomous responses to stress.

2023-03-12 | GSE226888 | GEO

Optimization of SILAC in human embryonic stem cells

Project description:We present a fully defined culture system (adapted Essential8 (E8) medium in combination with vitronectin) for human embryonic stem cells (hESC) that can be used for Stable Isotopic Labeling of Amino aCids (SILAC) purposes. Although a complete incorporation of the labels was observed after 4 days in culture, more than 50 % of all mass spectrometry (MS) precursors displayed a conversion of L-arginine (R) to L-proline (P) or L-glumatate (E) of 40 %. To reduce this arginine conversion, E8 medium was modified by adding (1) L-proline, (2) L-ornithine, (3) Nω-hydroxy-nor-L-arginine (Nor-NOHA) acetate or by (4) lowering the arginine concentration. Inhibition of arginine conversion was best obtained by adding 5mM L-ornithine, followed by 3.5 mM L-proline and by lowering arginine concentration to 99.5 µM. No major changes in the proteome (HDMSE data), pluripotency and cell amount could be observed for these adapted Essential8TM media, although sudden cell death was sometimes observed with the use of 99.5 µM L-arginine. In conclusion, we suggest using 5 mM L-ornithine to reduce arginine conversion.

2016-07-15 | PXD002859 | Pride

Functional genomics investigation of PfAdoMetDC/ODC co-inhibition of Plasmodium falciparum

Project description:Polyamines are ubiquitous components of all living cells and their depletion usually causes cytostasis, a strategy employed for treatment of West-African trypanosomiasis. To evaluate polyamine-depletion as an antimalarial strategy, cytostasis caused by the co-inhibition of S-adenosylmethionine decarboxylase/ornithine decarboxylase (PfAdoMetDC/ODC) in Plasmodium falciparum was studied with a comprehensive transcriptome, proteome and metabolome investigation. Highly synchronized cultures were sampled just before and during cytostasis and a novel zero time point definition was used to enable interpretation of results in lieu of the developmentally regulated control of gene expression in P. falciparum. Transcriptome analysis revealed the occurrence of a generalized transcriptional arrest just prior to the growth arrest due to polyamine-depletion. However, the abundance of 538 transcripts was differentially affected and included three perturbation-specific compensatory transcriptional responses: the increased abundance of the transcripts for lysine decarboxylase (LDC) and ornithine aminotransferase (OAT) as well as the decreased abundance of that for S-adenosylmethionine synthetase (AdoMet synthetase). Moreover, the latter two compensatory mechanisms were confirmed on both protein and metabolite levels confirming their biological relevance. In contrast with previous reports, the results provide evidence that P. falciparumrespond to alleviate the detrimental effects of polyamine-depletion via regulation of its transcriptome and subsequently the proteome and metabolome. Keywords: functional genomics, time course, reference design, drug exposure, stress response, polyamine depletion, cytostasis

2008-12-11 | GSE13578 | GEO

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription

Project description:Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against C. rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that cell-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as augments autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.

2022-10-06 | GSE214152 | GEO

ALDH RNA seq

Project description:Mono- and biallelic variants in the ALDH18A1 gene cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia. ALDH18A1 encodes the bifunctional enzyme pyrroline-5-carboxylate synthetase (P5CS) that plays a role in the de novo biosynthesis of proline and ornithine. Here we characterize a previously unreported homozygous ALDH18A1 variant (p.Thr331Pro) in four affected probands from two unrelated families, and demonstrate broad-based alterations in amino acid and antioxidant metabolism. These four patients exhibit variable developmental delay, neurological deficits, and loose skin. Functional characterization of the p.Thr331Pro variant demonstrated a lack of any impact on the steady-state level of the P5CS monomer or mitochondrial localization of the enzyme, but reduced incorporation of the monomer into P5CS oligomers. Using an unlabeled NMR-based metabolomics approach in patient fibroblasts and ALDH18A1-null human embryonic kidney cells expressing the variant P5CS, we identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione. Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell. RNA sequencing of patient fibroblasts revealed transcript abundance changes in several metabolic and ECM-related genes, adding further insight into pathogenic processes associated with impaired P5CS function. Together these findings shed new light on amino acid and antioxidant pathways associated with ALDH18A1-related disorders, and underscore the value of metabolomic and transcriptomic profiling to discover new pathways that impact disease pathogenesis.

2022-05-09 | GSE202424 | GEO

Arginine catabolism and polyamine biosynthesis pathway disparities within Francisella tularensis subpopulations

Project description:Arginine catabolism and polyamine biosynthesis pathway disparities within Francisella tularensis subpopulations

| PRJNA837875 | ENA

Chlorophyll biosynthesis under the control of arginine metabolism

Project description:In natural environments, photosynthetic organisms adjust their metabolism to cope with the fluctuating availability of combined nitrogen-sources, a growth limiting factor. For the acclimation, the dynamic degradation/synthesis of tetrapyrrolic pigments as well as of the amino acid arginine is pivotal; however, there was no evidence that these processes could be functionally coupled. Using co-immunopurification and spectral shift assays we found that in the cyanobacterium Synechocystis sp. PCC 6803 the arginine-related ArgD and CphB enzymes form protein complexes with Gun4, an essential factor for chlorophyll biosynthesis. Gun4 binds ArgD with high affinity, and the ArgD-Gun4 complex strongly accumulates in cells supplemented with ornithine, a key intermediate of the arginine pathway. Elevated ornithine levels restricted de novo synthesis of tetrapyrrolic pigments, which arrested the recovery from nitrogen deficiency. Our data reveals a direct cross-talk between tetrapyrrole biosynthesis and arginine metabolism that clarifies the importance of balancing photosynthetic pigment synthesis with nitrogen homeostasis.

2023-02-14 | MSV000091280 | MassIVE

Dietary enrichments cause alterations in metabolome, transcriptome and improve freeze-tolerance in larvae of the fruit fly (Drosophila melanogaster).

Project description:In this experiment, Drosophila melanogaster larvae were fed with Proline and Arginine compounds and showed a better tolerance to freezing compared to control larvae. Using a microarray approach, we investigated the alteration of transcriptome profiles in larvae fed with Proline or Arginine versus control larvae.

2019-01-01 | E-MTAB-3911 | biostudies-arrayexpress

DFMO effect on Th17 and iTreg cells (ATAC-Seq)

Project description:We studied the effects of polyamine pathway inhibitors on differentiation of nonpathogenic Th17 cellsin vitro. Here, we used difluoromethylornithine (DFMO), an irreversible inhibitor of ODC1, the enzyme that catalyzes the conversion of ornithine to putrescine.

2021-07-06 | GSE165088 | GEO

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