MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation

Autophagy, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 22

Published: Aug. 16, 2024

During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC deal with glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates cell survival under glucose-starvation conditions. MANF-mediated also promotes fatty acid oxidation in glucose-starved cells. Moreover, during starvation, SENP1-mediated de-SUMOylation increases cytoplasmic expression through inhibition MANF's nuclear translocation hence renders distribution MANF. mediates binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key regulator, mitochondria. Under conditions inhibits activity; nevertheless, CXXC motif alleviates RING II-domain restores its ligase activity. Furthermore, MANF-PRKN interactions are essential for growth metastasis. High predicts poor outcomes patients BC. Our results highlight prosurvival role suggesting as potential therapeutic target.

Language: Английский

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Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: March 27, 2024

Chemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to lack of specific targets. Given a modest response immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task this field. CD73 has emerged as novel immunotherapeutic target, given its elevated expression on tumor, stromal, cells, established role inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- NK-cell activation, while amplifying regulatory T cell activation. often leads increased activity, further suppressing anti-tumor While debulking tumor mass, chemotherapy also enriches heterogenous stem cells (CSC), potentially leading relapse. Therefore, drugs targeting both CD73, CSCs hold promise enhancing efficacy, overcoming resistance, clinical outcomes. However, safe effective have not been developed now. We used silico docking screen compounds that may be repurposed CD73. The efficacy these was investigated through flow cytometry, RT-qPCR, viability, tumorsphere formation, other vitro functional assays. For assessment translatability, patient-derived xenograft organotypic cultures were utilized. employed ovalbumin-expressing AT3 mouse model evaluate tumor-specific lymphocyte responses. identified quercetin luteolin, currently over-the-counter supplements, high complementarity with When luteolin combined chemotherapeutic paclitaxel triple-drug regimen, we found downregulation paclitaxel-enhanced CSC-promoting pathways YAP Wnt. required maintenance CD44highCD24low CSCs, co-targeting YAP, Wnt effectively suppressed growth human lines cultures. Furthermore, combination inhibited paclitaxel-enriched simultaneously improved infiltration syngeneic tumors. Conclusively, our findings elucidate significance impairing regimen clinically relevant platforms only underscores importance mechanistic investigations but paves way potential development new, safe, cost-effective therapeutic strategies TNBC.

Language: Английский

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UBE2T mediates SORBS3 ubiquitination to enhance IL‐6/STAT3 signaling and promote lung adenocarcinoma progression

Journal of Biochemical and Molecular Toxicology, Journal Year: 2024, Volume and Issue: 38(6)

Published: May 30, 2024

UBE2T is an oncogene in varying tumors, including lung adenocarcinoma (LUAD). SORBS3 important signaling regulatory protein that plays a crucial role many cancers. This study aimed to investigate whether promoted LUAD development by mediating the ubiquitination of and further explore its mechanism. Bioinformatics analysis was conducted examine expression tissues. Cell Counting Kit-8, Transwell, flow cytometry were employed analyze cellular functions SORBS3. Co-immunoprecipitation observe correlation between In vitro vivo experiments verified enhance interleukin-6/signal transducer activator transcription 3 (IL-6/STAT3) promote development. We observed significant downregulation tissues cells. Furthermore, inhibited proliferation, migration, invasion cells, while facilitating apoptosis vitro. enhanced IL-6/STAT3 degradation SORBS3, thereby promoting progression. Additionally, this mechanism validated xenograft animal model vivo. confirmed UBE2T-mediated progression, providing novel therapeutic target for LUAD.

Language: Английский

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Autophagy Deficiency Induced by SAT1 Potentiates Tumor Progression in Triple‐Negative Breast Cancer

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 29, 2024

Aggressive triple-negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role SAT1 (Spermidine/Spermine N1-acetyltransferase 1) in cancer, which needs to be further elucidated cancer. In this study, highly expressed TNBC signified worse patient prognoses. And knockdown effectively inhibited the proliferation and migration abilities cells vitro vivo. terms mechanism, transcription factor JUN enhanced transcriptional activity by binding promoter region. Then, protein cytoplasm engaged directly with YBX1 for sustaining stability via deubiquitylation mediated E3 ligase HERC5. Further, was found suppress autophagy remarkably stabilization mTOR mRNA accumulation YBX1-mediated methyl-5-cytosine (m5C) modification. These findings proved that drives progression through SAT1/YBX1/mTOR axis, may provide candidate therapy advanced TNBC.

Language: Английский

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CircCPA4 induces ASCT2 expression to promote tumor property of non‐small cell lung cancer cells in a miR‐145‐5p‐dependent manner

Thoracic Cancer, Journal Year: 2024, Volume and Issue: 15(10), P. 764 - 777

Published: Feb. 24, 2024

Abstract Background Non‐small cell lung cancer (NSCLC) is a type of that occurs in the cells respiratory tract, and its development influenced by regulation circular RNAs (circRNAs). However, role circRNA carboxypeptidase A4 (circCPA4) progression NSCLC underlying mechanism remain relatively clear. Methods The study utilized both real‐time quantitative polymerase chain reaction (RT‐qPCR) western blot techniques to evaluate levels circCPA4, microRNA‐145‐5p (miR‐145‐5p), alanine, serine, or cysteine‐preferring transporter 2 (ASCT2). To assess proliferation, counting kit‐8 (CCK8) 5‐ethynyl‐2′‐deoxyuridine (EdU) assays were performed. Apoptosis was determined using flow cytometry, while migration invasive capacity evaluated through transwell wound‐healing assays. Intracellular glutamine, glutamate, α‐KG measured specific kits. relationship between miR‐145‐5p circCPA4 ASCT2 confirmed dual‐luciferase reporter assay RNA immunoprecipitation assay. Results CircCPA4 elevated, downregulated tissues cells. Depletion significantly inhibited migration, invasion, intracellular α‐KG, promoted apoptosis. Moreover, knockdown delayed tumor growth vivo. Furthermore, found bind miR‐145‐5p, thereby regulating vitro. also identified as downstream target upregulation rescued effects overexpression on processes. Conclusion property modulating miR‐145‐5p/ASCT2 axis.

Language: Английский

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KMT2D‐mediated H3K4me1 recruits YBX1 to facilitate triple‐negative breast cancer progression through epigenetic activation of c‐Myc

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(7)

Published: July 1, 2024

Abstract Background Lysine methyltransferase 2D (KMT2D) mediates mono‐methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying KMT2D‐mediated modulates expression triple‐negative breast cancer (TNBC) progression unresolved. Methods and Results We recognized Y‐box‐binding protein 1 (YBX1) as a “reader” mark, point mutation YBX1 (E121A) disrupted this interaction. found that KMT2D cooperatively promoted cell growth metastasis TNBC cells vitro vivo. The levels were both upregulated tumour tissues correlated with poor prognosis for patients. Combined analyses ChIP‐seq RNA‐seq data indicated was co‐localized promoter regions c‐Myc SENP1, thereby activating their expressions cells. Moreover, we demonstrated activated SENP1 KMT2D‐dependent manner. Conclusion Our results suggest recruits facilitate through epigenetic activation SENP1. These together unveil crucial interplay between regulation progression, thus providing novel insights into targeting KMT2D‐H3K4me1‐YBX1 axis treatment. Highlights H3K4me1‐binding effector disrupts its binding H3K4me1. proliferation by colocalized increased predicts

Language: Английский

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Exosomal circ‐0100519 promotes breast cancer progression via inducing M2 macrophage polarisation by USP7/NRF2 axis

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(8)

Published: Aug. 1, 2024

Abstract Background Breast cancer (BC) is one of the most prevalent malignant tumours that threatens women health worldwide. It has been reported circular RNAs (circRNAs) play an important role in regulating tumour progression and microenvironment (TME) remodelling. Methods Differentially expression characteristics immune correlations circRNAs BC were verified using high‐throughput sequencing bioinformatic analysis. Exosomes characterised by nanoparticle transmission electron microscopy tracking The biological function circ‐0100519 development was demonstrated both vitro vivo. Western blotting, RNA pull‐down, immunoprecipitation, flow cytometry, luciferase reporter conducted to investigate underlying mechanism. Results Circ‐0100519 significant abundant tissues related poor prognosis. can be encapsulated into secreted exosomes, thereby promoting cell invasion metastasis via inducing M2‐like macrophages polarisation.Mechanistically, acted as a scaffold enhance interaction between deubiquitinating enzyme ubiquitin‐specific protease 7 (USP7) nuclear factor‐like 2 (NRF2) macrophages, USP7‐mediated deubiquitination NRF2. Additionally, HIF‐1α could upstream effector transcription. Conclusions Our study revealed exosomal potential biomarker for diagnosis prognosis, inhibitor PX‐478 may provide therapeutic target BC.

Language: Английский

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Exosomal circular RNAs in tumor microenvironment: An emphasis on signaling pathways and clinical opportunities

MedComm, Journal Year: 2024, Volume and Issue: 5(12)

Published: Nov. 24, 2024

Exosomes can regulate the malignant progression of tumors by carrying a variety genetic information and transmitting it to target cells. Recent studies indicate that exosomal circular RNAs (circRNAs) multiple biological processes in carcinogenesis, such as tumor growth, metastasis, epithelial-mesenchymal transition, drug resistance, autophagy, metabolism, angiogenesis, immune escape. In microenvironment (TME), circRNAs be transferred among cells, endothelial cancer-associated fibroblasts, microbiota, affecting initiation progression. Due high stability widespread presence circRNAs, they hold promise biomarkers for diagnosis prognosis prediction blood urine. addition, designing nanoparticles targeting utilizing derived from cells or stem provide new strategies cancer therapy. this review, we examined crucial role regulating tumor-related signaling pathways summarized transmission between various types their impact on TME. Finally, our review highlights potential diagnostic prognostic biomarkers, well suggesting clinical

Language: Английский

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Fibroblast Growth Factor Receptor 4 Promotes Triple‐Negative Breast Cancer Progression via Regulating Fatty Acid Metabolism Through the AKT/RYR2 Signaling

Cancer Medicine, Journal Year: 2024, Volume and Issue: 13(23)

Published: Dec. 1, 2024

Triple-negative breast cancer (TNBC) is the most aggressive subtype of cancer. Previous studies have found that fibroblast growth factor receptor 4 (FGFR4) plays a crucial role in tumor development and metastasis. However, potential underlying mechanisms FGFR4 progression TNBC remain unclear.

Language: Английский

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miR-28–3p suppresses gastric cancer growth and EMT-driven metastasis by targeting the ARF6/Hedgehog axis

Molecular and Cellular Probes, Journal Year: 2025, Volume and Issue: 79, P. 102010 - 102010

Published: Jan. 9, 2025

Language: Английский

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