Adding Polyamine Metabolism to the mTORC1 Toolkit in Cell Growth and Cancer

Gomes, Ana P.; Schild, Tanya; Blenis, John

doi:10.1016/j.devcel.2017.07.004

Cited by 14 publications

(10 citation statements)

References 10 publications

(19 reference statements)

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“…The PTEN–PI3K–mTOR complex 1 (mTORC1) pathway has been shown to be linked with polyamine metabolism in prostate cancer through the upregulation of AMD1 (REFS 45–47 ). Using an integrative metabolomics approach in both mouse and human prostate tumours, mTORC1 was shown to be required for increased AdoMetDC activity and dcAdoMet levels.…”

Section: Polyamines and Cancermentioning

confidence: 99%

Polyamine metabolism and cancer: treatments, challenges and opportunities

2018

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Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN-PI3K-mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy.

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Section: Polyamines and Cancermentioning

confidence: 99%

Polyamine metabolism and cancer: treatments, challenges and opportunities

2018

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“…Another gene related to the same gene family (namely Eukaryotic Translation Initiation Factor 4E Binding Protein 1, EIF4EBP1) was also found among the DEGs associated with porcine backfat thickness [88], supporting the evidence that EIF4E gene family may be involved in the processes associated with adipogenesis. mTORC1 signaling was also found to control polyamine synthesis [89]. Interestingly, high IMF pigs showed also a higher expression of Spermidine/ spermine N1-acetyltransferase (SAT1; log 2 FC = -1.35; adjusted P-value = 1.90E-04), an enzyme acting in the homeostasis of polyamines [90], that are molecules essential for cell growth [91].…”

Section: Plos Onementioning

confidence: 99%

Muscle transcriptome analysis identifies genes involved in ciliogenesis and the molecular cascade associated with intramuscular fat content in Large White heavy pigs

Zappaterra

Gioiosa²,

Chillemi

et al. 2020

PLoS ONE

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Intramuscular fat content (IMF) is a complex trait influencing the technological and sensorial features of meat products and determining pork quality. Thus, we aimed at analyzing through RNA-sequencing the Semimembranosus muscle transcriptome of Italian Large White pigs to study the gene networks associated with IMF deposition. Two groups of samples were used; each one was composed of six unrelated pigs with extreme and divergent IMF content (0.67 ± 0.09% in low IMF vs. 6.81 ± 1.17% in high IMF groups) that were chosen from 950 purebred individuals. Paired-end RNA sequences were aligned to Sus scrofa genome assembly 11.1 and gene counts were analyzed using WGCNA and DeSeq2 packages in R environment. Interestingly, among the 58 differentially expressed genes (DEGs), several were related to primary cilia organelles (such as Lebercilin 5 gene), in addition to the genes involved in the regulation of cell differentiation, in the control of RNA-processing, and G-protein and ERK signaling pathways. Together with cilia-related genes, we also found in high IMF pigs an over-expression of the Fibroblast Growth Factor 2 (FGF2) gene, which in other animal species was found to be a regulator of ciliogenesis. Four WGCNA gene modules resulted significantly associated with IMF deposition: grey60 (P = 0.003), darkturquoise (P = 0.022), skyblue1 (P = 0.022), and lavenderblush3 (P = 0.030). The genes in the significant modules confirmed the results obtained for the DEGs, and the analysis with "cyto-Hubba" indicated genes controlling RNA splicing and cell differentiation as hub genes. Among the complex molecular processes affecting muscle fat depots, genes involved in primary cilia may have an important role, and the transcriptional reprogramming observed in high IMF pigs may be related to an FGF-related molecular cascade and to ciliogenesis, which in the literature have been associated with fibro-adipogenic precursor differentiation.

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“…mTORC1 is a major energy-sensing and signaling hub that regulates anabolic processes and allows cells to adapt to an environment of nutrient surplus (Saxton and Sabatini, 2017). In the context of cancer, mTORC1 signaling is considered an important therapeutic target to slow down cell proliferation (Gomes et al, 2017). In the context of diabetes, on the other hand, the use of mTORC1 inhibitors has generated mixed outcomes (Ardestani et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration

et al. 2020

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Chronic exposure of pancreatic b-cells to excess glucose can lead to metabolic acceleration and loss of stimulus-secretion coupling. Here, we examined how exposure to excess glucose (defined here as concentrations above 5 mM) affects mTORC1 signaling and the metabolism of b-cells. Acute exposure to excess glucose stimulated glycolysis-dependent mTORC1 signaling, without changes in the PI3K or AMPK pathways. Prolonged exposure to excess glucose led to hyperactivation of mTORC1 and metabolic acceleration, characterized by higher basal respiration and maximal respiratory capacity, increased energy demand, and enhanced flux through mitochondrial pyruvate metabolism. Inhibition of pyruvate transport to the mitochondria decelerated the metabolism of b-cells chronically exposed to excess glucose and re-established glucose-dependent mTORC1 signaling, disrupting a positive feedback loop for mTORC1 hyperactivation. mTOR inhibition had positive and negative impacts on various metabolic pathways and insulin secretion, demonstrating a role for mTOR signaling in the long-term metabolic adaptation of b-cells to excess glucose.

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Adding Polyamine Metabolism to the mTORC1 Toolkit in Cell Growth and Cancer

Cited by 14 publications

References 10 publications

Polyamine metabolism and cancer: treatments, challenges and opportunities

Polyamine metabolism and cancer: treatments, challenges and opportunities

Muscle transcriptome analysis identifies genes involved in ciliogenesis and the molecular cascade associated with intramuscular fat content in Large White heavy pigs

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration

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