Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells
Ontology highlight
ABSTRACT:
SUBMITTER: Xiong D
PROVIDER: S-EPMC10979242 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundDiffuse large B-cell lymphoma (DLBCL) is predominant subtype of non-Hodgkin lymphoma and can be effectively treated. Nevertheless, a subset of patients experiences refractory or relapsed disease, highlighting the need for new therapeutic strategies.MethodsDepmap database based on CRISPR/Cas9 knock out analysis was employed to identify the essential gene SH3GL1, which encodes endophilin A2, as crucial for the proliferation and survival of DLBCL cells. Immunohistochemistry (IHC) staining was performed on the 126 paraffin-embedded clinical DLBCL samples to investigate the association between SH3GL1 expression levels and the prognosis. To investigate the specific mechanism modulated by SH3GL1 in the progression of DLBCL, an integrative approach was employed. This approach combined high-throughput sequencing technologies, such as Deep-DIA and LC-MS, with functional validation techniques, including CRISPR/Cas9 gene editing, xenograft models, and molecular pathway analyses.ResultsOur study found that high expression levels of SH3GL1 correlate with poor prognosis in a cohort of 126 newly diagnosed DLBCL patients, underscoring its significance in disease progression. Mechanistically, we found that SH3GL1 deficiency triggers ferritin heavy chain 1 (FTH1)-mediated ferroptosis, specifically ferritinophagy-induced ferroptosis, in DLBCL cells. Additionally, high expression of SH3GL1 suppresses doxorubicin-induced ferroptosis. Cancer cells' resistance to conventional therapies is associated with increased sensitivity to ferroptosis.ConclusionsThese findings emphasise SH3GL1 as a promising prognostic biomarker and a potential therapeutic target in DLBCL, offering new avenues for treatment strategies aimed at overcoming drug resistance and improving patients' outcomes.Key pointsElevated SH3GL1 expression in DLBCL patients was associated with a negative prognosis. SH3GL1 plays a crucial role in promoting DLBCL cell survival through the regulation of FTH1-mediated ferroptosis and doxorubicin resistance.
| S-EPMC11879899 | biostudies-literature
Project description: Not available
| S-BSST1072 | biostudies-other
Project description:Comparing the effects of artesunate versus DMSO in three DLBCL cell lines, we found a decrease in cell viability to 80%-60%. Over increasing artesunate dosage,we found increasing ROS generation and lipid peroxidation. In combination with the Ferrostatin-1 rescue experiment, we conclude that cell death induced by artesunate is ferroptotic. We compared the transcriptome of the U2932 cell line with and without 100µm artesunate in triplicate. A ferroptosis gene signature is shown to be enriched among the upregulated genes of this comparison. GPX4 protein expression was shown to be downregulated after artesunate in U2932 cells, but not in the rescue experiment with Ferrostatin-1. MT1G gene expression was identified as required for artesunate-mediated ferroptosis via targeted suppression by shRNAs. We present significantly decreased cell viability when combining artesunate with doxorubicin, suggesting a potential translation into clinic for treatment of ABC and GCB DLBCL.
2024-03-06 | GSE260741 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of DLBCL patients, first-line multi-agent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. Here, a compound library targeting epigenetic modulators was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate (DMF) or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 (FSP1) expression and to thus protect GCB DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
2023-08-01 | GSE231871 | GEO
Project description:New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon-nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND-Dox-TF, CDT) was 10-100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. SIGNIFICANCE: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.
| S-EPMC9177130 | biostudies-literature
Project description:In a retrospective analysis of clinical data from 587 DLBCL (diffuse large B-cell lymphoma) patients in China, 13.8% of cases were associated with HBV (hepatitis B virus) infection, leading to distinct clinical features and poorer prognosis. Moreover, HBV infection has a more pronounced impact on the survival of the GCB (germinal center B-cell-like) type DLBCL patients compared to the ABC (activated B-cell-like) type. In this study, we found that the expression of LncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was downregulated in the HBV-infected GCB-type DLBCL patients, and the HBV core protein (HBX) directly inhibited the MALAT1 expression in DLBCL cells. Notably, the overexpression of HBX could attenuate the Erastin-induced ferroptosis in the GCB-type DLBCLs, while MALAT1 re-expression restored sensitivity in the HBX-overexpressing DLBCLs in vitro and in vivo. Mechanistically, MALAT1 competitively hindered SFPQ (splicing factor proline and glutamine-rich) from effectively splicing the pre-mRNA of SLC7A11 (solute carrier family 7 member 11), due to a shared TTGGTCT motif, which impeded the SLC7A11 pre-mRNA maturation and hence diminished its negative regulation on ferroptosis. Together, our study identified HBX's role in inhibiting MALAT1 expression, promoting SFPQ-mediated splicing of SLC7A11 pre-mRNA, and reducing the GCB-type DLBCL sensitivity to Erastin-induced ferroptosis. Combined with the recent studies that ferroptosis may be involved in the occurrence and development of DLBCL, these findings explain our clinical data analysis that DLBCL patients with low expression of MALAT1 have poorer prognosis and shorter overall survival, and provide a valuable therapeutic target for the HBV-infected GCB-type DLBCL patients.
| S-EPMC11557927 | biostudies-literature
Project description: Not available
| S-EPMC8377611 | biostudies-literature
Project description:IntroductionEmerging evidence has revealed that long noncoding RNA (lncRNA) play important role in almost all kinds of human cancers. LINC00908 has been reported to be involved in the development of prostate cancer, colorectal cancer and gastric cancer which was functioned as an oncogene. However, the potential biology role and molecular mechanism of LINC00908 in diffuse large B-cell lymphoma are still unclear.MethodsLINC00908 and miR-671-5p expression were evaluated in DLBCL tissues and cell lines using RT-qPCR. CCK-8 and transwell assay were used to analyze the in vitro role of LINC00908 in DLBCL progression. The xenograft model was used to explore the in vivo role of LINC00908 in DLBCL growth. The physical interaction between LINC00908 and miR-671-5p was confirmed using bioinformatics analysis and a dual luciferase assay, RIP and RNA pull down.ResultsThe expression of LINC00908 was markedly up-regulated in diffuse large B-cell lymphoma tissues and cell lines, and the decreased expression of LINC00908 significantly inhibited diffuse large B-cell lymphoma cell proliferation and invasion. Then, we revealed that LINC00908 directly interacted with miR-671-5p, which was down-regulated in diffuse large B-cell lymphoma cells and highly expressed with LINC00908 knockdown. Moreover, luciferase reporter assays and RNA immunoprecipitation (RIP) assay further proved that miR-671-5p is a direct target of LINC00908 in diffuse large B-cell lymphoma cells. Rescue experiments were also performed, and we confirmed that LINC00908 acts as an oncogene role in diffuse large B-cell lymphoma through miR-671-5p. Finally, the influence of LINC00908 silence significantly inhibited diffuse large B-cell lymphoma growth in vivo.ConclusionLINC00908 promotes malignancy of diffuse large B-cell lymphoma through regulating miR-671-5p.
| S-EPMC8096343 | biostudies-literature
Project description:The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) is the immunochemotherapy-based R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Resistance to treatment, intrinsic or acquired, is observed in approximately 40% of patients with DLBCL, who thus require novel interventions to survive. To identify biomarkers for cytotoxic response assessment, microRNAs (miRNAs) associated with doxorubicin sensitivity were determined by combining global miRNA expression profiling with systematic dose-response screens in 15 human DLBCL cell lines. One candidate, miR-34a, was tested in functional in vitro studies and in vivo in a retrospective clinical cohort. High expression of miR-34a was observed in cell lines sensitive to doxorubicin, and upregulation of miR-34a is documented here to increase doxorubicin sensitivity in in vitro lentiviral transduction assays. High expression of miR-34a had a prognostic impact using overall survival as outcome. With risk stratification of DLBCL samples based on resistance gene signatures (REGS), doxorubicin-responsive samples had statistically significant upregulated miR-34a expression. Classification of the DLBCL samples into subset-specific B cell-associated gene signatures (BAGS) revealed differentiation-specific expression of miR-34a. Our data further support FOXP1 as a target of miR-34a, suggesting that downregulation of FOXP1 may sensitize DLBCL cells to doxorubicin. We conclude that miRNAs, in particular miR-34a, may have clinical utility in DLBCL patients as both predictive and prognostic biomarkers.
2018-01-15 | GSE72648 | GEO
Project description: Not available
| S-EPMC10894040 | biostudies-literature