GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE225628 | GEO | 2023/08/01
REPOSITORIES: GEO
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Project description:GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis
| PRJNA936846 | ENA
Project description:Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after cancer drug treatment. These cells are the living proof of response to a drug, and an interesting experimental subject for biomarker discovery. Here, we performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. First, we showed that eribulin induces a specific secretome in DTP cells as compared to other microtubule targeting agents. Then, we selected and functionally validated growth differentiation factor 15 (GDF15) as a protein significantly over-secreted upon eribulin treatment. Interestingly, GDF15 expression is low/absent in cells that are sensitive to eribulin, strongly upregulated during the response to the drug, and downregulated when stable resistance is ultimately established. Proteomic results were confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. Unexpectedly, despite its biomarker potential for eribulin response, we found that GDF15 is also paradoxically required for survival of DTP cells, although once full resistance to eribulin is established, GDF15 expression largely disappears. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function conditions. These results pointed to a potential benefit of simultaneous targeting of GDF15/GFRAL and eribulin, and indeed we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired eribulin resistance, and possibly other cytotoxic drugs. Overall, the combination of cytotoxic agents with targeted agents aimed specifically at DTP cells could be an effective therapeutic approach for metastatic breast cancer patients.
2023-01-09 | PXD034037 | Pride
Project description:Psychological stress activates the autonomic nervous system to protect organisms through an integrated response involving changes to both behavior and metabolism. Epinephrine is an important driver of this response, activating adipose tissue lipolysis3and inducing anxiety-like behavior. Interestingly, anxiety correlates with circulating free fatty acid levels and can be alleviated by a b-blocker that does not cross the blood brain barrier suggesting a peripheral signal linking metabolism with behavior, however, to date this has not been defined. Herein, we identify that the most upregulated secreted gene product induced by epinephrine within white adipose tissue of mice is growth differentiating factor 15 (GDF15). This increase in GDF15 occurs within one hour and is not observed in liver, brown adipose, kidney, or skeletal muscle, and is also observed with the more specific b2/3-agonist, CL316,243. Genetic inhibition of adipose triglyceride lipase (ATGL), the rate limiting enzyme for the release of free fatty acids in white adipose tissue, or genetic deletion of b-adrenergic receptors, blocks b-adrenergic induced increases in GDF15. Increases in circulating GDF15 are not derived from adipocytes but instead require free fatty acid-induced stimulation of macrophages within white adipose tissue. Remarkably, anxiety-like behavior elicited by epinephrine or restraint stress are eliminated in mice lacking the GDF15 receptor, GFRAL. Importantly in patients with severe burns, increases in catecholamines are associated with GDF15 and this relationship is eliminated with the b-blocker propranolol. These data provide important insight into the mechanisms linking metabolism and behavior and suggest that inhibition of GDF15-GFRAL signaling may be important for reducing acute anxiety.
2024-05-15 | GSE267183 | GEO
Project description:Anorexia and other side effects of chemotherapy significantly limit the clinical applications of these chemotherapeutic agents, with underlying mechanisms still unclear. A growing body of research reveals that elevated levels of circulating GDF15 after chemotherapy are essential in initiating anorexia and other side effects by activating GFRAL+ neurons in the brainstem. However, the full array of context-dependent transcriptional regulators controlling Gdf15 expression remains to be defined. This study reports that chemotherapy drugs acutely stimulate liver GDF15 production via selective activation of the hepatic stress sensor IRE1α, thereby controlling circulating GDF15 levels. Genetic ablation of hepatic IRE1α reduces circulating GDF15 and alleviates anorexia and body weight loss following chemotherapy drug treatments in tumor-bearing mice. Mechanistically, chemotherapy drugs activate hepatic IRE1α RNase activity to produce the active form of the transcription factor XBP1 to promotes the expression of Gdf15 gene in hepatocytes. Moreover, treatment with pharmacological IRE1α RNase inhibitor effectively suppresses liver Gdf15 expression and circulating GDF15 levels, resulting in improvements in chemotherapy-induced anorexia and body weight loss. Our results reveal a stress-responsive mechanism that mediates communication between the liver and brain. This mechanism can be targeted pharmacologically to alleviate anorexic side effects that accompany chemotherapy-induced body weight loss.
2024-04-22 | GSE235695 | GEO
Project description:Oxidative stress is a major pathogenic mechanism in Parkinson’s disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. Unfortunately, the GSH level is greatly decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. Besides, we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. Given that dopamine agonist treatment in PD is limited by their intolerable side effects and diminished effectiveness over time, we anticipate dimerizing PKM2 to be a new strategy for PD treatment.
2020-02-04 | GSE143164 | GEO
Project description:Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
2024-07-30 | E-MTAB-12831 | biostudies-arrayexpress
Project description:Growth Differentiation Factor 15 (GDF15) is a divergent member of the TGF-β superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine BPD models, and GDF15 loss exacerbates oxidative stress and decreases viability in vitro in pulmonary epithelial and endothelial cells. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15-/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% O2) for 5 days after birth. The mice were euthanized on PND 21. Gdf15 -/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Upon exposure to hyperoxia, female mice had higher alveolar simplification in the Gdf15-/- group than the female WT group. Gdf15-/- and WT mice showed no difference in the degree of the arrest in angiogenesis upon exposure to hyperoxia. Gdf15-/- mice showed lower macrophage count in the lungs compared to WT mice. Our results suggest that Gdf15 deficiency decreases the tolerance to hyperoxic lung injury with evidence of sex-specific differences.
2023-07-20 | GSE211744 | GEO
Project description:GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment and may mediate metformin effects by long-term GDF15-GFRAL agonism. If GFRAL+ neurons acutely regulate glucose and energy homeostasis is however underexplored. Here, we report that cell-specific activation of GFRAL+ neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat. Metabolomic analysis of blood and transcriptomics of muscle and fat indicate alterations in ketogenesis, insulin signaling, adipose tissue differentiation and mitogenesis, or energy fluxes. Our findings reveal that acute GFRAL+ neuron activation induces endocrine and gluco- and thermoregulatory responses associated with nausea and torpor. While chronic activation of GFRAL signaling promotes weight loss in obesity, these results show that acute activation of GFRAL+ neurons causes hypothermia and hyperglycemia.
2024-03-21 | GSE255540 | GEO
Project description:The TGFβ cytokine family member, GDF15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brain stem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake, we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated, pathophysiologic signals to suppress nutrient uptake and absorption.
2021-01-01 | GSE160257 | GEO