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:As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, “cuproptosis” represents copper-dependent cell death, a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake still lacks systematic analysis. Based on quantitative proteomics, we revealed the crosstalk between copper stress and cuproptosis in cancer cells. Copper stress not only couples with cuproptosis, but also leads to reactive oxygen species (ROS) stress, oxidative damage and cell cycle arrest. In cancer cells, a feedback cytoprotection mechanism involving cuproptosis mediators was discovered. During copper treatment, the activation of glutamine transporters and the loss of Fe-S cluster proteins are the facilitators and results of cuproptosis, respectively. Through copper depletion, glutathione (GSH) blocks the cuproptosis process, rescues the activation of glutamine transporters, and prevents the loss of Fe-S cluster proteins, expect for protecting cancer cells from apoptosis, protein degradation and oxidative damage. Our results are significative for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.
2022-11-17 | PXD037278 | Pride
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:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248083 | GEO
Project description:Cuproptosis is characterized by the aggregation of lipoylated components of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. Dysregulation of copper homeostasis and resulting cuproptosis induction is an emerging area of interest for cancer therapy. However, mechanisms of cancer cell evasion of cuproptosis are not well understood. Here, we found that the cuproptosis process is accompanied by activation of the Wnt/β-catenin pathway. Mechanistically, copper binds to PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed that the β-catenin/TCF4 transcriptional complex directly binds to the promoter region of ATP7B, a protein responsible for the efflux of copper ions from the cell, inducing its expression and reducing intracellular copper accumulation, thereby inhibiting cuproptosis. Knockdown of TCF4 or pharmacological blockade of the Wnt/β-catenin pathway increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and may provide a precision medicine strategy for cancer treatment by selectively inducing cuproptosis
2023-11-21 | GSE248084 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most prevalent hepatic pathology worldwide. However, the precise molecular mechanisms for NAFLD are still not sufficiently explained. Recently, a new mode of cell death (cuproptosis) is found. However, the relationship between NAFLD and cuproptosis remains unclear. We analyzed three public datasets to identify cuproptosis-related genes stably expressed in NAFLD. Then, we performed a series of bioinformatics analyses to explore the relationship between NAFLD and cuproptosis-related genes. Finally, 3 normal control mouse and 3 high-fat diet (HFD)-induced NAFLD C57BL/6J mouse models were established to carry out transcriptome analysis.
2023-04-30 | E-MTAB-11980 | biostudies-arrayexpress
Project description:MYC-driven Group-3 medulloblastomas (MB) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identified upregulationof dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenasecomplex (PDC) in a subset of Group-3 MB with poor prognosis. DLAT was induced by c-MYC and targeting DLAT lowered TCA-cycle metabolism and glutathione synthesis in Group-3 MB cells. We also noted upregulation of isocitrate dehydrogenase 1 (IDH1) in Group-3 MB. Remarkably, genetic and pharmacologic suppression of IDH1 epigenetically reduced c-MYC and downstream DLAT levels. DLAT is a central regulator of cuproptosis, a copper-dependent cell death mechanism induced by the copper ionophore elesclomol. DLAT expression in Group-3 MB cells correlated with increased sensitivity to cuproptosis. Elesclomol was CNS-penetrant and suppressed tumor growth in vivo in Group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill Group-3MB by cuproptosis.
2025-04-10 | GSE278880 | 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