Ontology highlight
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PROVIDER: PRJNA1327564 | ENA |
REPOSITORIES: ENA
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Project description:Apoptotic Cells Enhances Chemotherapy Resistance
| PRJNA1325040 | ENA
Project description:Dysregulation of the NF-κB pathway is frequently observed in cancers, contributing to therapy resistance by inhibiting apoptosis. In this study, we identify RNF25, an E3 ubiquitin ligase, as a key regulator of signal transduction, inflammation, immune responses, and apoptosis. RNA sequencing (RNA-seq) analysis following RNF25 knockdown revealed significant alterations in key apoptotic regulators and NF-κB signaling components, highlighting the role of RNF25 in apoptotic resistance and therapeutic response. Pathway enrichment analysis further demonstrated disruptions in pro-survival and inflammatory signaling pathways, suggesting that RNF25 knockdown enhances apoptotic sensitivity and may influence treatment efficacy. This dataset provides valuable insights into potential therapeutic targets for overcoming treatment resistance.
2025-03-26 | GSE293002 | GEO
Project description:Type II germ cell tumors (GCTs) are the most common neoplasia in young men of age 14-45 years. It is generally accepted that GCTs arise from a common precursor lesion, called germ cell neoplasia in situ (GCNIS), eventually developing into seminomas or non-seminomas, such as (embryonal carcinomas, ECs). The latter stem-cell like EC can further differentiate into teratomas (TE), yolk-sac tumors (YST), or choriocarcinomas (CC). Even though cisplatin-based chemotherapy is an efficacious standard of care during the management of GCT patients, the development of cisplatin resistance remains a major obstacle. As such, the surrounding tumor microenvironment and its secreted factors could endorse the development of drug resistance. These stromal cells, including immune cells (e.g. macrophages, T-lymphocytes), endothelial cells, and fibroblasts, can influence tumor cells by promoting proliferative and anti-apoptotic signaling pathways. Vice versa, microenvironmental cells can be influenced by tumor cells as well. For the identification of secreted proteins, cell lysates and supernatants from seven human germ cell tumor cell lines (seminoma: TCam-2; embryonal carcinoma (EC): 2102EP, NCCIT; choriocarcinoma (CC): JAR, JEG-3), yolk-sac tumor (YST): GCT72; 1411H) and five human cell types from the microenvironment (fibroblasts: MPAF, HVHF2; M2 macrophages: THP-1-M2; T-lymphocytes: JURKAT; endothelial cells: HUVEC) have been evaluated using liquid chromatography coupled with mass spectrometry (LC-MS).
2022-10-13 | PXD031329 | Pride
Project description:Platinum-based chemotherapy causes genetic damage and induces apoptosis in ovarian cancer cells. Enhancing the ability to resist platinum drug-induced DNA damage and apoptotic stress is critical for tumor cells to acquire drug resistance. Here, we found that Y-box binding protein 1 (YBX1) was highly expressed in platinum-resistant patient-derived organoids (PDOs) and was a crucial gene for alleviating platinum-induced stress and maintaining drug resistance characteristics in ovarian cancer cells.
2023-09-19 | PXD045503 |
Project description:Traditional ideas hold that the accumulation of mitochondria in thermogenic adipose tissue, namely brown and beige fat, helps to increase energy expenditure (EE), thereby alleviating obesity and metabolic disorders. However, recent studies in mice have shown that knocking out key proteins that maintain mitochondrial function can inhibit the activation of thermogenic fat while somehow protecting the mice from high-fat diet (HFD)–induced metabolic disorders. Therefore, the specific role of adipose mitochondria in metabolic benefits needs further analysis. Here, our use of non-biased sequencing-based screening identified YY1 as a key player in maintaining mitochondrial function in thermogenic adipose tissue. YY1 promotes the transcription of electron transport chain (ETC) genes during thermogenesis; thus, YY1 adipose knockout (YAKO) mice showed reduced body temperature and EE under cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced obesity and insulin resistance, which can be attributed to a repression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 in adipocytes directs glucose metabolism toward lactate, enhances the uptake of glutamine, and promotes the production of anti-inflammatory spermidine. Blocking spermidine production can reverse the beneficial metabolic effects observed in YAKO mice. In summary, our findings reveal a metabolic reprogramming pathway centered on adipose mitochondria; that is, although blocking YY1 reduced the mitochondria content, it generated spermidine and alleviated adipose inflammation, therefore leads to a thermogenic capacity-metabolic benefits uncoupling phenomenon.
2024-08-26 | GSE272637 | GEO
Project description:Dysregulation of the NF-κB pathway is frequently observed in cancers, contributing to therapy resistance by inhibiting apoptosis. In this study, we identify RNF25, an E3 ubiquitin ligase, as a key regulator of signal transduction, inflammation, immune responses, and apoptosis. RNA sequencing (RNA-seq) analysis following RNF25 knockdown revealed significant alterations in key apoptotic regulators and NF-κB signaling components, highlighting the role of RNF25 in apoptotic resistance and therapeutic response. Pathway enrichment analysis further demonstrated disruptions in pro-survival and inflammatory signaling pathways, suggesting that RNF25 knockdown enhances apoptotic sensitivity and may influence treatment efficacy. This dataset provides valuable insights into potential therapeutic targets for overcoming treatment resistance.
2025-03-25 | GSE291116 | GEO
Project description:Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine, an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, Alexidine binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Unlike chemotherapy, Alexidine eradicates baseline MMP and MMP heterogeneity within leukemic populations, a functional signature linked to stemness and chemoresistance. Intriguingly, this heterogeneity originates not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis, which leukemia cells selectively activate to bypass chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.
2025-07-11 | MTBLS12596 | MetaboLights
Project description:Comprehensive Model Description
Overview
This model simulates the cellular response to DNA damage under conditions of ATM/ATR deficiency—such as in ataxia telangiectasia—and predicts the potential benefits of drug repositioning with Omaveloxolone and spermidine. It integrates several interconnected modules: DNA damage production and repair, ATM/ATR–p53 signaling, NRF2/KEAP1 regulation, spermidine-induced autophagy (with additional positive modulation of ATR signaling), and downstream p53 effectors involved in cell fate decisions.
1. DNA Damage Production and Repair Module
Basal DNA Damage Production:
DNA damage is continuously generated at a constant rate, representing both endogenous processes and low-level environmental stress. This reaction acts as a source term for the DNA_damage species.
Repair Pathways:
Several mechanisms work to reduce DNA damage:
ATM-Mediated Repair: Active ATM facilitates the direct repair of DNA damage.
ATR-Mediated Repair: Active ATR, in cooperation with CHK1, repairs DNA damage.
NRF2-Mediated Repair: Active NRF2 triggers antioxidant responses that reduce DNA damage.
Autophagy-Mediated Repair: The autophagy pathway, induced by spermidine, repairs DNA damage in a saturable manner (modeled using Michaelis–Menten kinetics). This ensures that even a significant pulse of damage is only partially repaired, leaving a nonzero steady-state level.
2. ATM/ATR–p53 Signaling Module
ATM and ATR Activation:
DNA damage, along with a positive input from TOPBP1, converts inactive ATM and ATR to their active forms. Under ATM/ATR-deficient conditions (as in ataxia telangiectasia), the activation is severely reduced, resulting in higher levels of unrepaired DNA damage.
p53 Activation:
Both ATM_active and ATR_active phosphorylate and activate p53. Active p53 then acts as a central integrator of the DNA damage signal.
Regulatory Proteins:
HDAC4:
HDAC4 cycles between inactive and active states. Its active form can attenuate p53 activity.
TOPBP1:
TOPBP1 is activated in a DNA damage–dependent manner and helps promote ATR activation.
CK2:
CK2 is a constitutively active kinase that supports TOPBP1 activation.
3. NRF2/KEAP1 Module and Omaveloxolone
NRF2 Activation:
DNA damage stimulates the conversion of NRF2_inactive to NRF2_active. Active NRF2 enhances antioxidant defenses and promotes DNA repair.
KEAP1-Mediated Degradation:
Under normal conditions, KEAP1 targets NRF2_inactive for degradation, keeping NRF2 activity low.
Modulation by Omaveloxolone:
Omaveloxolone is modeled as a constant (boundary) species. It inhibits KEAP1’s activity, thereby reducing NRF2 degradation. This shifts the balance in favor of increased NRF2_active, which boosts the cell’s antioxidant and repair responses.
4. Spermidine-Induced Autophagy and Positive Modulation of ATR Signaling
Spermidine is modeled as a constant species and has two major effects:
Induction of Autophagy:
Spermidine promotes the conversion of Autophagy_inactive to Autophagy_active. The active autophagy machinery repairs DNA damage using a saturable (Michaelis–Menten) mechanism. This pathway helps clear DNA damage but is limited by its maximum capacity.
Enhancement of ATR Signaling:
Spermidine also positively modulates ATR signaling by enhancing the CK2-mediated activation of TOPBP1. In the model, the effective rate of TOPBP1 activation is increased proportionally to the concentration of spermidine. This is represented by a modulation factor, where the effective rate constant for TOPBP1 activation is multiplied by a term that increases with spermidine concentration. The boosted TOPBP1_active level in turn enhances ATR activation, partially compensating for the loss of ATM/ATR function.
5. Downstream p53 Targets: Cell Fate Decisions
Activated p53 regulates cell fate by inducing the production of several downstream effectors:
p21:
p21 is produced in response to p53 activation and is associated with cell cycle arrest and senescence. Its production is balanced by a degradation reaction.
BAX and PUMA:
Both BAX and PUMA are pro-apoptotic proteins. They are produced in proportion to p53_active and are subsequently degraded. Their relative levels help determine whether the cell will undergo apoptosis.
6. Reaction Kinetics (Qualitative Overview)
Mass-Action and Michaelis–Menten Kinetics:
Most reactions in the model are governed by mass-action kinetics. For example, activation and deactivation reactions (such as ATM activation by DNA damage or p53 activation by ATM/ATR) follow simple proportional relationships.
Saturable Repair Processes:
The autophagy-mediated DNA repair reaction uses Michaelis–Menten kinetics to reflect a saturation effect; when DNA damage is high, the repair rate approaches a maximum value, ensuring that not all damage is cleared immediately.
Modulatory Effects:
Spermidine increases the effective rate of TOPBP1 activation (and hence ATR activation) via a modulation term that is proportional to its concentration. Omaveloxolone reduces the degradation rate of NRF2 by inhibiting KEAP1.
Biological Implications and Model Utility
ATM/ATR Deficiency:
In ataxia telangiectasia, ATM/ATR functions are diminished, leading to increased DNA damage. The model simulates this scenario and examines how alternative pathways (NRF2-mediated repair, autophagy, and enhanced ATR signaling via spermidine) help mitigate the damage.
Drug Repositioning Predictions:
The model can be used to predict the outcomes of repositioning drugs:
Omaveloxolone is expected to stabilize NRF2, enhancing antioxidant defenses and reducing DNA damage.
Spermidine acts dually by promoting autophagy (with a saturable repair capacity) and by boosting ATR signaling via TOPBP1 activation.
Cell Fate Outcomes:
The downstream p53 targets (p21, BAX, and PUMA) serve as markers for cell cycle arrest/senescence and apoptosis. By simulating the dynamics of these proteins, the model can predict whether a cell is likely to survive, arrest its cycle, or undergo apoptosis based on the integrated response to DNA damage and drug interventions.
Conclusion
This detailed and comprehensive model integrates multiple layers of the cellular response to DNA damage in ATM/ATR-deficient conditions. It includes upstream damage sensing, multiple repair pathways (including direct kinase-mediated repair, antioxidant responses via NRF2, and autophagy-mediated repair), and downstream effectors that determine cell fate. Omaveloxolone and spermidine are modeled to specifically modulate the NRF2/KEAP1 pathway and ATR signaling (via TOPBP1 activation), respectively. This framework provides a robust platform for exploring drug repositioning strategies and predicting cellular outcomes in diseases such as ataxia telangiectasia.
2025-11-25 | MODEL2503190002 | BioModels
Project description:The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy-sensitive versus resistant cell populations. Here, we report that mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical samples from children with T-ALL treated on recent Dana-Farber Cancer Institute or Children’s Oncology Group clinical trials, we found that loss-of-function mutations in any of three core components of PRC2 (EZH2, EED or SUZ12) were associated with resistance to mitochondrial apoptosis. In human T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action, including dexamethasone, doxorubicin and vincristine. PRC2 loss induced apoptosis resistance via transcriptional upregulation of the LIM domain transcription factor CRIP2, and subsequent downstream upregulation of the mitochondrial chaperone TRAP1. Importantly, TRAP1 overexpression was necessary to induce resistance to chemotherapy-induced apoptosis downstream of PRC2 inactivation, and pharmacologic inhibition of TRAP1 synergized with dexamethasone and doxorubicin. These findings demonstrate the importance of relative mitochondrial apoptotic priming as a prognostic factor in T-ALL, and implicate mitochondrial chaperone function as a molecular determinant of response to cancer chemotherapy, suggesting a rationale for targeted therapeutic intervention.
2018-10-18 | GSE112147 | GEO
Project description:Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance
2017-01-26 | GSE86839 | GEO