Acute myeloid leukaemia (AML) comprises a heterogeneous group of hematologic neoplasms characterized by diverse combinations of genetic, phenotypic and clinical features representing a major ...challenge for the development of targeted therapies. Metabolic reprogramming, mainly driven by deregulation of the nutrient‐sensing pathways as AMPK, mTOR and PI3K/AKT, has been associated with cancer cells, including AML cells, survival and proliferation. Nevertheless, the role of these metabolic adaptations on the AML pathogenesis is still controversial. In this work, the metabolic status and the respective metabolic networks operating in different AML cells (NB‐4, HL‐60 and KG‐1) and their impact on autophagy and survival was characterized. Data show that whereas KG‐1 cells exhibited preferential mitochondrial oxidative phosphorylation metabolism with constitutive co‐activation of AMPK and mTORC1 associated with increased autophagy, NB‐4 and HL‐60 cells displayed a dependent glycolytic profile mainly associated with AKT/mTORC1 activation and low autophagy flux. Inhibition of AKT is disclosed as a promising therapeutical target in some scenarios while inhibition of AMPK and mTORC1 has no major impact on KG‐1 cells’ survival. The results highlight an exclusive metabolic profile for each tested AML cells and its impact on determination of the anti‐leukaemia efficacy and on personalized combinatory therapy with conventional and targeted agents.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Caloric restriction intervention alleviates α-synuclein toxicity in yeast-aged cells.•Caloric restriction and abrogation of TOR1 result in decreased Sir2 activity in cells expressing ...α-synuclein.•Opposite roles of Tor1 and Sir2, under caloric restriction intervention, result in homeostatic autophagy levels.
Alpha-synuclein (syn) is the main component of proteinaceous inclusions known as Lewy bodies (LBs), which are implicated in the pathogenesis of the neurodegenerative diseases known as synucleinopathies, like Parkinson’s disease (PD). Aging is a major risk factor for PD and thus, interventions that delay aging will have promising effects in PD and other synucleinopathies. Caloric restriction (CR) is the only non-genetic intervention shown to promote lifespan extension in several model organisms. CR has been shown to alleviate syn toxicity and herein we confirmed the same effect on the yeast model for synucleinopathies during chronological lifespan. The data gathered showed that TOR1 deletion also results in similar longevity extension and abrogation of syn toxicity. Intriguingly, these interventions were associated with decreased autophagy, which was maintained at homeostatic levels. Autophagy maintenance at homeostatic levels promoted by CR or TOR1 abrogation in syn-expressing cells was achieved by decreasing Sir2 levels and activity. Furthermore, the opposite function of Tor1 and Sir2 in autophagy is probably associated with the maintenance of autophagy activity at homeostatic levels, a central event linked to abrogation of syn toxicity promoted by CR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with ...suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
α‐Synuclein (aSyn) toxicity is associated with cell cycle alterations, activation of DNA damage responses (DDR), and deregulation of autophagy. However, the relationships between these phenomena ...remain largely unknown. Here, we demonstrate that in a yeast model of aSyn toxicity and aging, aSyn expression induces Ras2‐dependent growth signaling, cell cycle re‐entry, DDR activation, autophagy, and autophagic degradation of ribonucleotide reductase 1 (Rnr1), a protein required for the activity of ribonucleotide reductase and dNTP synthesis. These events lead to cell death and aging, which are abrogated by deleting RAS2, inhibiting DDR or autophagy, or overexpressing RNR1. aSyn expression in human H4 neuroglioma cells also induces cell cycle re‐entry and S‐phase arrest, autophagy, and degradation of RRM1, the human homologue of RNR1, and inhibiting autophagic degradation of RRM1 rescues cells from cell death. Our findings represent a model for aSyn toxicity that has important implications for understanding synucleinopathies and other age‐related neurodegenerative diseases.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants ...with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci,
(
= 2.19 × 10
) and
(
= 6.28 × 10
) were associated with the risk of CRC. Mechanistically, the
allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with
(
= 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (
= 0.0038) and serum levels of en-RAGE (
= 0.0068).
allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (
= 0.0088 and
= 0.0076, respectively), CD14+CD16- cell levels in blood (
= 0.0068) and serum levels of CCL19 and cortisol (
= 0.0052 and
= 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the
and
loci in the pathogenesis of CRC, likely through the modulation of host immune responses.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The cancer metabolic reprogramming allows the maintenance of tumor proliferation, expansion and survival by altering key bioenergetics, biosynthetic and redox functions to meet the higher demands of ...tumor cells. In addition, several metabolites are also needed to perform signaling functions that further promote tumor growth and progression. These metabolic alterations have been exploited in different cancers, including acute myeloid leukemia, as novel therapeutic strategies both in preclinical models and clinical trials. Here, we review the complexity of acute myeloid leukemia (AML) metabolism and discuss how therapies targeting different aspects of cellular metabolism have demonstrated efficacy and how they provide a therapeutic window that should be explored to target the metabolic requirements of AML cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The free radical theory of aging posits oxidative damage to macromolecules as a primary determinant of lifespan. Recent studies challenge this theory by demonstrating that in some cases, longevity is ...enhanced by inactivation of oxidative stress defenses or is correlated with increased, rather than decreased reactive oxygen species and oxidative damage. Here we show that, in Saccharomyces cerevisiae, caloric restriction or inactivation of catalases extends chronological lifespan by inducing elevated levels of the reactive oxygen species hydrogen peroxide, which activate superoxide dismutases that inhibit the accumulation of superoxide anions. Increased hydrogen peroxide in catalase-deficient cells extends chronological lifespan despite parallel increases in oxidative damage. These findings establish a role for hormesis effects of hydrogen peroxide in promoting longevity that have broad implications for understanding aging and age-related diseases.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Proteostasis is a cellular housekeeping process that refers to the healthy maintenance of the cellular proteome that governs the fate of proteins from synthesis to degradation. Perturbations of ...proteostasis might result in protein dysfunction with consequent deleterious effects that can culminate in cell death. To deal with the loss of proteostasis, cells are supplied with a highly sophisticated and interconnected network that integrates as major players the molecular chaperones and the protein degradation pathways. It is well recognized that the ability of cells to maintain proteostasis declines during ageing, although the precise mechanisms are still elusive. Indeed, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan in a variety of ageing models. Therefore, an improved understanding of the interventions/mechanisms that contribute to cellular protein quality control will have a huge impact on the ageing field. This mini-review centers on the current knowledge about the major pathways that contribute for the maintenance of Saccharomyces cerevisiae proteostasis, with particular emphasis on the developments that highlight the multidimensional nature of the proteostasis network in the maintenance of proteostasis, as well as the age-dependent changes on this network.
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