Repurposing MDM2 Inhibitor RG7388 For TP53-Mutant NSCLC: A p53-Independent Pyroptotic Mechanism via ROS/p-p38/NOXA/Caspase-3/GSDME Axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1215332 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32119608_1.fastq.gz | Fastqsanger.gz | |||
| SRR32119608_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 3 of 3 |
Similar Datasets
Project description:Non-small cell lung cancer (NSCLC) is highly malignant with limited treatment options due to the inherent tumoral heterogeneity and acquired resistance towards chemotherapy and immunotherapy. RG7388 was previously reported to have anticancer activity against TP53WT NSCLC which was designed as MDM2 inhibitor triggering p53/PUMA axis-dependent apoptosis. However, RG7388 exhibited p53-independent anticancer effect against TP53mutant NSCLC in our current research, the underlying mechanisms of which were still uncertain. Here, we reported that RG7388 specifically induced NOXA/Caspase-3 axis dependent apoptosis and gasdermin E (GSDME)-mediated secondary pyroptosis in TP53mutant NSCLC using in silico and multiple biological methods. Mechanically, we identified accumulated reactive oxygen species (ROS) served as the pivotal factor in NOXA upregulation and p38 MAPK pathway activation in RG7388 treated TP53mutant NSCLC by using two ROS scavengers N-acetylcysteine (NAC) and Ferrostatin-1 (Fer-1) respectively. Furthermore, pharmacologic inhibition of p38 MAPK signaling by SB203580 rescued RG7388 induced ROS-dependent NOXA accumulation and subsequent apoptosis and pyroptosis, thus suggesting a leading role of ROS/phosphorylated p38 MAPK (p-p38)/NOXA/Caspase-3 axis in RG7388 induced TP53mutant NSCLC cell death. Taken together, our work unraveled a novel mechanism of selective targeting of mutant p53 derived cancers via ROS/p-p38-mediated NOXA accumulation that could have potential therapeutic implications given the relative lack of direct mutant p53 targeting strategies in cancer. Moreover, A strong positive correlation between p-p38 and NOXA expression was confirmed by using an NSCLC tissue microarray and immunohistochemical (IHC) staining. Clinical data analysis suggested that the p-p38/NOXA axis could serve as a potential indicator for predicting overall survival (OS) in NSCLC patients.
2025-06-12 | GSE287938 | GEO
Project description: Not available
| S-EPMC12170848 | biostudies-literature
Project description:Cisplatin (CDDP) is one of the most active chemotherapeutic agents used for ovarian cancer; however, primary or acquired platinum resistance is associated with poor prognosis. Nelfinavir (NFV), an HIV protease inhibitor, has demonstrated anti-tumor activity in multiple cancer models, but its interaction with CDDP in ovarian cancer has yet to be demonstrated. In this study, we investigated whether combined CDDP and NFV treatment provides a therapeutic advantage in platinum-resistant ovarian cancer cells. Drug synergy between NFV and CDDP was assessed using cell viability assays and Loewe additivity modelling. Apoptotic and pyroptotic signaling were evaluated by immunoblotting, mitochondrial membrane potential analysis, lactate dehydrogenase release, and caspase inhibition. Transcriptomic changes were assessed by bulk mRNA sequencing followed by differential gene expression analysis and gene set enrichment analysis. NFV synergized with CDDP to reduce the viability of platinum-resistant ovarian cancer cells and promoted a regulated lytic cell death phenotype involving apoptotic and pyroptotic features. Combination treatment induced caspase-8 and caspase-3 activation, with downstream gasdermin E (GSDME) processing. Inhibition of caspase-3 significantly attenuated cell death, while caspase-8 inhibition rescued viability and prevented Bid cleavage, caspase-3 activation, and GSDME cleavage. These effects occurred in the context of enhanced endoplasmic reticulum stress, increased DNA damage with reduced DNA repair, and impaired Akt-driven survival signaling. Together, these findings establish that NFV synergizes with CDDP in platinum-resistant ovarian cancer cells by promoting a caspase-8-dependent apoptotic-to-secondary pyroptotic response, supporting further investigation of NFV as a candidate drug for repurposing to enhance platinum-based therapy.
2026-07-10 | GSE338229 | GEO
Project description:Acute myeloid leukemia (AML) is a challenging hematological malignancy characterized by high relapse rates and limited treatment options. Compound corilagin, an ellagitannin derived from ethnopharmacological plants, shows promise as an anti-cancer agent, although its anti-leukemic effects remain poorly understood. This study aims to investigate whether corilagin induces cell death in AML cells and explore the underlying mechanisms. In AML cells, corilagin induces pyroptosis, as characterized by the formation of pyroptotic bubbles, increased lactate dehydrogenase (LDH) release and a higher proportion of propidium iodide (PI)-positive cells. Corilagin activates caspase-3, which in turn cleaves gasdermin E (GSDME) to generate GSDME-NT, promoting pyroptosis. Additionally, corilagin activates thioredoxin-interacting protein (TXNIP), and the knockdown of TXNIP rescues cells from corilagin-induced pyroptosis. Corilagin reduces cell viability and induces pyroptosis in primary AML cells, and in an AML cell-derived xenograft (CDX) mouse model, it inhibits leukemia progression and prolongs survival. These findings imply that corilagin induces pyroptosis in AML through the TXNIP/caspase-3/GSDME pathway, presenting a prospective novel therapeutic strategy for AML treatment.
2026-02-11 | GSE315428 | GEO
Project description:It is widely acknowledged that gasdermin family proteins, which are known as the executors of pyroptosis, undergo protease-mediated cleavage prior to inducing pyroptosis. Here, we unexpectedly discovered a non-canonical form of pyroptosis mediated by full-length GSDME (FL-GSDME) without any proteolytic cleavage. Upon intense ultraviolet (UV) irradiation-triggered DNA damage, hyperactivation of nuclear PARP1 led to extensive formation of poly(ADP-ribose) (PAR) polymers and then release to the cytoplasm.These PAR polymers activate PARP5 to catalyze GSDME PARylation, resulted in a conformational change in GSDME that relieved autoinhibition imposed by its C terminus on the N terminus. On the other hand, intense UV irradiation boosted mitochondrial fission-dependent generation of mitochondrial reactive oxygen species (mito-ROS), further promoting cytochrome c-catalyzed peroxidation of cardiolipin. This lipid-ROS signal was then sensed by PARylated-GSDME and then induced oxidative oligomerization of GSDME, which facilitated FL-GSDME plasma membrane targeting for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARPs activity and lipid-ROS also induced sequential modifications i.e., PARylation and oxidation of FL-GSDME and synergistically promoted pyroptotic cell death. Overall, our findings elucidate a novel mechanism underlying cleavage-independent function of GSDME in executing cell demise, further enriching the paradigms and cognition of FL-GSDME-mediated non-canonical pyroptosis.
2024-06-17 | PXD051840 | Pride
Project description:It’s an effective anti-cancer strategy to study natual products for activating GSDME-mediated pyroptosis through targeting PARP-1 in NSCLC. Previously, we found that a novel flavonoid Japoflavone B (JFB) has exhibited an excellent inhibitory activity against cancer cell proliferation in vitro study, but its in vivo and mechanism study are still unknown. Herein, JFB could specifically inhibit the proliferation of NSCLC cells, but not normal lung epithelial cells. JFB induced inflammatory pyroptosis through the activation of caspase-3 and GSDME cleavage. JFB also activated caspase-3/7/9 activities and triggered mitochondria-mediated apoptosis. Its inhibitory activity would be significantly reversed with the caspase-3 or GSDME deficiencies and their specific inhibitors. JFB could targetedly inhibit PARP-1 activity, and promote DNA damage and ROS accumulation. Meanwhile, JFB could significantly promote p-p38 and p53 expression. Then, JFB induced cell cycle G2/M arrest by reprogramming the expression of cyclins, CDKs and CKIs. Moreover, its cytotoxicity could be dramatically reversed with the ROS scavenger and p38 inhibitor. In vivo, JFB exhibited a comparable anti-tumor activity to that of Dox with no significant tissue toxicity. Our data firstly revealed that JFB functions as a selective and non-NAD-based PARP inhibitor with high affinity and low toxicology, which makes it potential to develop as a lead anti-cancer compound. As well, JFB promoted caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC cells. Our study was further enriched the specific mechanism that PARP inhibitor could trigger caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC cells.
2025-11-09 | GSE281636 | GEO
Project description:Acute kidney injury(AKI) is associated with an increased risk of chronic kidney disease(CKD). There is still a lack of effective prevention for AKI-CKD transition. In the present study, we simultaneously explored the contribution of GSDMD and GSDME in folic acid (FA)-induced nephropathy, a model mimicking the essential components of the AKI-CKD transition. We found that blockage of both GSDMD and GSDME-mediated pyroptosis could have accumulative protection against FA-induced AKI-CKD transition. GSDME-mediated pyroptosis played a crucial role in tubular cell damage. GSDMD could exert important functions in infiltration of inflammatory cells and NETs formation. Pyroptotic tubular cells triggered NETs generation and macrophage polarization. NETs promoted macrophage-to-myofibroblast transition. Our results illustrated the orchestration of GSDMD and GSDME in AKI-CKD transition, providing new insights into the molecular mechanism for the clinical dilemma.
2024-10-31 | GSE245446 | GEO
Project description: Not available
| S-EPMC9718385 | biostudies-literature
Project description:To revealed the significant involvement of GSDME-mediated pyroptosis in the pathogenesis and development of ICI-LI
2024-12-23 | GSE280068 | GEO
Project description:Investigation of NOXA dependent apoptosis in pancreatic cancer cell lines with CRISPR/Cas9 mediated knockouts for NOXA and RUNX1 including parental cell lines.
2025-04-03 | GSE148188 | GEO