Cell Death Discovery最新文献_第8页

Lead bioaccumulation in human breast cancer tissue is associated with DNA instability and cell death resistance. 铅在人乳腺癌组织中的生物蓄积与DNA不稳定和细胞死亡抵抗有关。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-15 DOI: 10.1038/s41420-025-02676-6

Manuel Scimeca, Erica Giacobbi, Rita Bonfiglio, Renata Sisto, Stefano Casciardi, Francesca Servadei, Daniel R S Middleton, Julia Bischof, Maria Paola Scioli, Giorgio Modesti, Eleonora Candi, Gerry Melino, Alessandro Mauriello

{"title":"Lead bioaccumulation in human breast cancer tissue is associated with DNA instability and cell death resistance.","authors":"Manuel Scimeca, Erica Giacobbi, Rita Bonfiglio, Renata Sisto, Stefano Casciardi, Francesca Servadei, Daniel R S Middleton, Julia Bischof, Maria Paola Scioli, Giorgio Modesti, Eleonora Candi, Gerry Melino, Alessandro Mauriello","doi":"10.1038/s41420-025-02676-6","DOIUrl":"10.1038/s41420-025-02676-6","url":null,"abstract":"Lead (Pb) is increasingly recognized for its potential to alter cellular processes and contribute to cancer development. Although Pb is classified as a probable carcinogen by the IARC, the clinical evidence for its role in breast cancer is inconsistent and limited to epidemiological studies yet. The aim of this study was to investigate the Pb bioaccumulation in human breast cancer tissues by correlating its concentration with specific cancer factors related to carcinogenesis. Biopsy samples from 26 breast cancer patients were collected for molecular investigations (DNA and RNA sequencing), histological analysis, and the assessment of Pb concentration by ICP-MS. Data reported here revealed Pb bioaccumulation in all breast cancer samples, with a significant positive correlation between Pb levels and both Tumoral Mutational Burden and Microsatellite Instability, suggesting an association of Pb with genomic instability in human breast cancer samples. Additionally, Pb was associated with increased expression of cell death-related molecules such as BCL2 and p53. This association allows us to hypothesize a potential involvement of Pb in affecting cell death resistance. Interestingly, Pb concentration showed no correlation to other established prognostic and predictive biomarkers of breast cancer, such as PAM50. Thus, Pb concentration may represent a new independent risk factor for breast cancer development. This study provides new insights into the role of Pb bioaccumulation in breast cancer and suggests that environmental exposure to Pb may contribute to more aggressive tumor behavior through mechanisms involving genomic instability and resistance to apoptosis.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"383"},"PeriodicalIF":7.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Illuminating photoreceptors: TGFβ signaling modulates the severeness of retinal degeneration. 照明光感受器：TGFβ信号调节视网膜变性的严重程度。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-15 DOI: 10.1038/s41420-025-02685-5

Aaron Schroers, Andreas Neueder, Isabel Massoudy, Andrea E Dillinger, Süleyman Ergün, Barbara M Braunger, Anja Schlecht

{"title":"Illuminating photoreceptors: TGFβ signaling modulates the severeness of retinal degeneration.","authors":"Aaron Schroers, Andreas Neueder, Isabel Massoudy, Andrea E Dillinger, Süleyman Ergün, Barbara M Braunger, Anja Schlecht","doi":"10.1038/s41420-025-02685-5","DOIUrl":"10.1038/s41420-025-02685-5","url":null,"abstract":"In various ocular diseases, retinal degeneration (RD) is a clinical symptom that can lead to irreversible vision loss. These diseases include age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Retinal degeneration describes a process during which the retina deteriorates due to the gradual death of photoreceptor cells. Although extensive research has been pursued to identify the underlying pathomechanisms, the precise molecular mechanisms that leads to photoreceptor death remains unclear. In this study, we combined the mouse model of light-induced photoreceptor degeneration with single-cell RNA sequencing to decipher the transcriptional response of degenerating photoreceptor cells. We additionally performed pseudotime analysis of gene expression changes for both the control and light-damaged photoreceptor clusters to analyze the extent of degeneration following a virtual trajectory of severeness. We found a transcriptional heterogeneity of rod photoreceptors in both control and degenerative conditions, and mapped several rod clusters which strongly differ in their transcriptional profile. We defined one of these clusters as the predominant disease-associated rod cluster, containing the most severely damaged rod cells. Pseudotime analysis demonstrated a strong regulation of TGFβ signaling and the RNA-induced silencing complex (RISC) in light-damaged photoreceptors suggesting a pivotal role of these mediators in retinal degeneration.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"384"},"PeriodicalIF":7.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual role mechanisms of regulated cell death in apical periodontitis: from pathogenic destruction to therapeutic potential. 根尖牙周炎中调节细胞死亡的双重作用机制：从致病性破坏到治疗潜力。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-15 DOI: 10.1038/s41420-025-02686-4

Yu Cao, Shipeng Yang, Quzhen Baima, Yuqi Zhen, Xinyue Hang, Xiuping Meng

{"title":"Dual role mechanisms of regulated cell death in apical periodontitis: from pathogenic destruction to therapeutic potential.","authors":"Yu Cao, Shipeng Yang, Quzhen Baima, Yuqi Zhen, Xinyue Hang, Xiuping Meng","doi":"10.1038/s41420-025-02686-4","DOIUrl":"10.1038/s41420-025-02686-4","url":null,"abstract":"Apical periodontitis (AP), a highly prevalent infectious disease driven by pathogenic microorganisms residing in periapical tissues, orchestrates a dynamic interplay between microbial virulence and host immune defenses. Emerging evidence indicates that these pathogens critically manipulate regulated cell death (RCD) pathways to subvert immune surveillance and dictate periapical bone remodeling outcomes. While RCD has traditionally been viewed as a dichotomy between pro-inflammatory destruction and anti-inflammatory repair, recent advances reveal its context-dependent duality, shaped by microbial-immune crosstalk. Despite growing interest in this field, current literature lacks a comprehensive synthesis delineating the dual-pathological impact of RCD mechanisms in AP progression, particularly their beneficial versus detrimental roles. This review critically evaluates the molecular mechanisms of RCD and crosstalk among its forms, delineating its dual roles in immune defense versus bone destruction during AP progression. We synthesize current understanding of RCD pathways in AP pathogenesis and explore therapeutically targeting these mechanisms to modulate disease outcomes. Furthermore, we explore the feasibility of developing therapeutic strategies for AP based on RCD targets and propose novel research directions to advance understanding and treatment of this condition.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"386"},"PeriodicalIF":7.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protein arginine methyltransferase 1 stimulates basal cell proliferation and migration to maintain corneal epithelial homeostasis. 蛋白精氨酸甲基转移酶1刺激基底细胞增殖和迁移，维持角膜上皮稳态。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-15 DOI: 10.1038/s41420-025-02684-6

Jia Yang, Mingzheng Hu, Mulin Yang, Hua Ni, Jun Zhou, Dengwen Li, Jie Ran, Min Liu

{"title":"Protein arginine methyltransferase 1 stimulates basal cell proliferation and migration to maintain corneal epithelial homeostasis.","authors":"Jia Yang, Mingzheng Hu, Mulin Yang, Hua Ni, Jun Zhou, Dengwen Li, Jie Ran, Min Liu","doi":"10.1038/s41420-025-02684-6","DOIUrl":"10.1038/s41420-025-02684-6","url":null,"abstract":"The corneal epithelium is a constantly self-renewing, stratified squamous tissue that protects the inner eye from external stimuli. The organization of the corneal epithelium involves multiple biological activities, including basal cell proliferation and centripetal migration. However, the underlying molecular mechanisms remain unclear. Herein, we identify protein arginine methyltransferase 1 (PRMT1) as a key regulator of corneal epithelial homeostasis. We exploited an inducible Prmt1 knockout mouse model and observed apparent disruption in the corneal epithelial homeostasis. PRMT1-deficient mice exhibited significant corneal epithelial thinning, as evidenced by histological and immunofluorescence staining with epithelium-specific markers. Further investigation showed that the epithelial thinning in these mice resulted from the dysfunction of basal cells. Immunostaining and 5-ethynyl-2'-deoxyuridine incorporation assays demonstrated that PRMT1 depletion significantly inhibited the proliferation and migration of basal cells, whereas no apparent apoptosis-related abnormalities were observed in these cells. Moreover, scratch wound healing assays revealed that knockdown of PRMT1 expression or inhibition of its catalytic activity significantly impaired the migration of corneal epithelial cells. Overall, our findings uncover a critical role for PRMT1 in controlling basal cell proliferation and migration to maintain corneal epithelial homeostasis, thereby providing potential therapeutic targets for the treatment of corneal diseases.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"385"},"PeriodicalIF":7.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GLUT3 enhances chemosensitivity in glioblastoma by transporting temozolomide and capecitabine. GLUT3通过转运替莫唑胺和卡培他滨增强胶质母细胞瘤的化学敏感性。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-14 DOI: 10.1038/s41420-025-02664-w

Honglin Diao, Yuxin Sun, Xiaojia Zhou, Qikai Wang, Mingyue Wang, Keyu Chen, Zhihua Huang, Jianlei Wei, Zeping Li, Yaxin Lou, Zebin Mao, Wenhua Yu

{"title":"GLUT3 enhances chemosensitivity in glioblastoma by transporting temozolomide and capecitabine.","authors":"Honglin Diao, Yuxin Sun, Xiaojia Zhou, Qikai Wang, Mingyue Wang, Keyu Chen, Zhihua Huang, Jianlei Wei, Zeping Li, Yaxin Lou, Zebin Mao, Wenhua Yu","doi":"10.1038/s41420-025-02664-w","DOIUrl":"10.1038/s41420-025-02664-w","url":null,"abstract":"Glioblastoma multiforme (GBM), the most aggressive brain cancer, is highly resistant to chemotherapy, which profoundly affects patient survival and prognosis. Temozolomide (TMZ), the sole first-line chemotherapeutic agent for GBM, faces substantial challenges in overcoming this resistance. Despite the belief that TMZ is well-absorbed in the small intestine and can effectively cross the blood-brain barrier due to its small molecular size, emerging evidence suggests that its uptake is not merely through passive diffusion across the lipid bilayer but is regulated by Wnt signaling. However, the precise mechanism governing TMZ uptake remains elusive. GLUT3, which is highly expressed in GBM and primarily functions as a glucose transporter, has emerged as a promising therapeutic target. This study demonstrates that GLUT3 upregulation in GBM cells enhances sensitivity to both TMZ and capecitabine (CAPE). Uptake assays revealed that GLUT3 overexpression (OE) or knockdown (KD) significantly influenced the uptake of these chemotherapeutic agents. We further validated the interaction between GLUT3 and TMZ/CAPE through molecular docking, dynamics simulations, and MST assay. Site-directed mutagenesis identified eight amino acids involved in GLUT3-mediated binding and transport of TMZ and CAPE. A mouse xenograft model confirmed that GLUT3 OE significantly increases TMZ/CAPE uptake and cytotoxicity, particularly under fasting conditions. Our findings establish GLUT3 as a multifunctional transporter for TMZ, CAPE, and glucose, thereby enhancing GBM chemosensitivity. These results challenge the prevailing notion that GLUT3's role in tumors is solely related to glucose transport. Our work suggests tailoring chemotherapy based on GLUT3 expression level in GBM patients and reevaluating GLUT inhibitors in combination with chemotherapeutic agents.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"382"},"PeriodicalIF":7.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation. 在低氧化应激模型中靶向缺氧诱导因子-1可保护视网膜色素上皮细胞免于细胞死亡和代谢失调。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-14 DOI: 10.1038/s41420-025-02675-7

Annika Schubert, Maria Eduarda Lobo Barbosa da Silva, Tabea Ambrock, Orbel Terosian, Anna Malyshkina, Claudia Padberg, Safa Larafa, Johann Matschke, Joachim Fandrey, Yoshiyuki Henning

{"title":"Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation.","authors":"Annika Schubert, Maria Eduarda Lobo Barbosa da Silva, Tabea Ambrock, Orbel Terosian, Anna Malyshkina, Claudia Padberg, Safa Larafa, Johann Matschke, Joachim Fandrey, Yoshiyuki Henning","doi":"10.1038/s41420-025-02675-7","DOIUrl":"10.1038/s41420-025-02675-7","url":null,"abstract":"Oxidative stress and hypoxia lead to dysfunction of retinal pigment epithelium (RPE) cells and are hallmarks of diseases such as age-related macular degeneration (AMD), the most common blinding disease in the elderly population. We have previously shown that a combination of these two risk factors, i.e. hypoxidative stress, exacerbates RPE cell death by ferroptosis. Hypoxia leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. In the present study, we have therefore investigated the roles of HIF-1 and HIF-2 in RPE cell death in a human RPE cell line under hypoxidative stress. For this purpose, we conducted siRNA-mediated knockdowns of the α-subunits of HIF-1 and HIF-2. We found that especially iron metabolism, in particular the expression of transferrin receptor 1 (TFR1) was affected by HIF-1α silencing, resulting in decreased intracellular iron levels and ferroptosis susceptibility. We also found that heme oxygenase 1 (HO-1) contributed to cell death by hypoxidative stress. In addition, we also observed that cell metabolism was improved by HIF-1α silencing under hypoxia, most likely contributing to the protective effect. Furthermore, we identified an FDA-approved small molecule inhibitor, Vorinostat, to downregulate HIF-1α, TFR1, and HO-1 and improve cell metabolism, which eventually resulted in a full rescue of RPE cells from hypoxidative stress-induced cell death. In conclusion, this study highlights the importance of considering targeted HIF inhibition as a promising approach to protect RPE cells from degeneration.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"380"},"PeriodicalIF":7.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Empowering hypoxia to convert cold tumors into hot tumors for breast cancer immunotherapy. 利用缺氧将冷肿瘤转化为热肿瘤用于乳腺癌免疫治疗。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-14 DOI: 10.1038/s41420-025-02682-8

Lu Liu, Danping Wu, Zhiwen Qian, Ying Jiang, Yilan You, YiDa Wang, Feng Zhang, Xin Ning, Jie Mei, Jabed Iqbal, Yanfang Gu, Yan Zhang

{"title":"Empowering hypoxia to convert cold tumors into hot tumors for breast cancer immunotherapy.","authors":"Lu Liu, Danping Wu, Zhiwen Qian, Ying Jiang, Yilan You, YiDa Wang, Feng Zhang, Xin Ning, Jie Mei, Jabed Iqbal, Yanfang Gu, Yan Zhang","doi":"10.1038/s41420-025-02682-8","DOIUrl":"10.1038/s41420-025-02682-8","url":null,"abstract":"Breast cancer remains the most common cancer among women globally and a leading cause of cancer-related death. Despite the promise of immunotherapy for triple-negative breast cancer (TNBC), its overall effectiveness is hindered by the cold tumor microenvironment (TME), characterized by sparse immune cell infiltration. This review explores the pivotal role of hypoxia in shaping the breast cancer TME and its influence on immunotherapy efficacy. As a defining feature of most solid tumors, including breast cancer, hypoxia drives aggressive tumor behavior, metastasis, and treatment resistance. The hypoxic TME promotes immune evasion and maintains the cold tumor phenotype. Targeting hypoxia offers a potential strategy for transforming cold breast tumors into hot tumors that respond more effectively to immunotherapy. This review consolidates existing insights into the interplay between hypoxia, tumor immunophenotypes, and immunotherapy in breast cancer. By analyzing the mechanisms through which hypoxia modulates the TME and immune response, it proposes innovative strategies to enhance immunotherapy outcomes. This comprehensive analysis lays the groundwork for developing more effective combination therapies to improve breast cancer prognosis.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"381"},"PeriodicalIF":7.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comprehensive view on chemotherapy-free management of acute myeloid leukemia by using venetoclax in combination with targeted and/or immune therapies. venetoclax联合靶向和/或免疫疗法治疗急性髓系白血病的无化疗综合观察

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-13 DOI: 10.1038/s41420-025-02678-4

David Kegyes, Andrei Tat, Alin Stefan Vizitiu, Daiana Vazar-Tripon, Radu Ilie, Adrian Bogdan Tigu, Diana Cenariu, Anamaria Bancos, Sabina Iluta, Ciprian Jitaru, Madalina Nistor, Radu Tomai, Diana Gulei, Mihnea Zdrenghea, Hermann Einsele, Gabriel Ghiaur, Carlo M Croce, Ciprian Tomuleasa

{"title":"Comprehensive view on chemotherapy-free management of acute myeloid leukemia by using venetoclax in combination with targeted and/or immune therapies.","authors":"David Kegyes, Andrei Tat, Alin Stefan Vizitiu, Daiana Vazar-Tripon, Radu Ilie, Adrian Bogdan Tigu, Diana Cenariu, Anamaria Bancos, Sabina Iluta, Ciprian Jitaru, Madalina Nistor, Radu Tomai, Diana Gulei, Mihnea Zdrenghea, Hermann Einsele, Gabriel Ghiaur, Carlo M Croce, Ciprian Tomuleasa","doi":"10.1038/s41420-025-02678-4","DOIUrl":"10.1038/s41420-025-02678-4","url":null,"abstract":"A hallmark of cancer biology is resistance to apoptosis. BCL-2 is an anti-apoptotic molecule that is being overexpressed in several myeloid diseases, such as acute myeloid leukemia and myelodysplastic syndromes, but also in several lymphoid cancers, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphomas and multiple myeloma. Venetoclax (VEN) is a BCL-2 small molecule inhibitor. Data about its structure, biochemical characteristics and in vitro efficacy against several blood cancer cell lines were first reported in 2013. Shortly after, the first clinical trials reported that single-agent VEN provides no long-term survival benefits. In contrast, when used in combination, VEN led to significantly improved outcomes and eventually to its first US FDA approvals in 2018. As the modern approach to treating hematological malignancies are the chemotherapy-free regimen, in the current manuscript, we provide a comprehensive view on all available therapies that are considered to be chemotherapy-free, with a special emphasis on acute myeloid leukemia (AML), where phase I-III clinical trials have provided the most data.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"379"},"PeriodicalIF":7.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12350645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AXL tyrosine kinase inhibitor TP-0903 induces ROS trigger neuroblastoma cell apoptosis via targeting the miR-335-3p/DKK1 expression. AXL酪氨酸激酶抑制剂TP-0903通过靶向miR-335-3p/DKK1表达诱导ROS触发神经母细胞瘤细胞凋亡。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-13 DOI: 10.1038/s41420-025-02681-9

Tsai-Yi Tseng, Shao-Hsuan Kao, Shun-Fa Yang, Yi-Chen Lin, Chu-Liang Lin, Juei-Liang Chen, Chien-Min Chen, Yi-Hsien Hsieh

{"title":"AXL tyrosine kinase inhibitor TP-0903 induces ROS trigger neuroblastoma cell apoptosis via targeting the miR-335-3p/DKK1 expression.","authors":"Tsai-Yi Tseng, Shao-Hsuan Kao, Shun-Fa Yang, Yi-Chen Lin, Chu-Liang Lin, Juei-Liang Chen, Chien-Min Chen, Yi-Hsien Hsieh","doi":"10.1038/s41420-025-02681-9","DOIUrl":"10.1038/s41420-025-02681-9","url":null,"abstract":"Neuroblastoma (NB) is an aggressive cancer and has poor prognosis in children. TP-0903, a multi-kinase inhibitor, shows inhibitory effects on NB but the mechanistic act is not completely explored. Here, we aimed to explore the anticancer activity of TP-0903 against NB cells and its underlying mechanism. In this study, our findings showed that TP-0903 ( ≥ 50 nM) significantly inhibited the growth of SH-SY5Y and Neuro-2a cells. Further results revealed that TP-0903 remarkably triggered cell apoptosis, mitochondrial membrane potential (MMP) lose, and caspase activation. Microarray assay, qRT-PCR, and Western blotting results indicated that DKK1 was downregulated by TP-0903. Notably, DKK1 is upregulated in NB tissues as comparing to normal tissues. Moreover, silencing DKK1 promoted TP-0903-induced apoptosis and caspase activation, and predicted the binding of TP-0903 to DKK1. In addition, we found that 3'-UTR of DKK1 had a potential target region for miR-335-3p and TP-0903 upregulated miR-335-3p expression. Of important, miR-335-3p mimic combined with TP-0903 provoked higher apoptosis and caspase activation than TP-0903 alone. We also observed that TP-0903 increased cellular reactive oxygen species (ROS), and inhibition of ROS reduced the apoptosis, PARP cleavage, and miR-335-3p, while increasing DKK1 in response to TP-0903. Finally, we demonstrated that TP-0903 significantly diminished the tumor growth and DKK1 expression in xenograft mice. Collectively, our findings indicate that TP-0903 triggers apoptotic cell death of NB cells, attributing to the ROS-mediated miR-335-3p upregulation and the consequent DKK1 downregulation.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"378"},"PeriodicalIF":7.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12350951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cannabichromene: integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy. 大麻红素：细胞凋亡、铁下垂和内源性大麻素信号在胰腺癌治疗中的综合调节。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-08-11 DOI: 10.1038/s41420-025-02674-8

Yu-Na Hwang, Ju-Hee Park, Han-Heom Na, Tae-Hyung Kwon, Jin-Sung Park, Sehyun Chae, Young Taek Oh, Keun-Cheol Kim

{"title":"Cannabichromene: integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy.","authors":"Yu-Na Hwang, Ju-Hee Park, Han-Heom Na, Tae-Hyung Kwon, Jin-Sung Park, Sehyun Chae, Young Taek Oh, Keun-Cheol Kim","doi":"10.1038/s41420-025-02674-8","DOIUrl":"10.1038/s41420-025-02674-8","url":null,"abstract":"Cannabichromene (CBC: C21H3O2, M.W.: 314.46 g) is a non-psychotropic phytocannabinoid derived from Cannabis sativa (hemp), and its potential therapeutic properties have attracted increasing attention. Specifically, it has demonstrated strong anti-inflammatory effects in animal models of edema through non-CB receptor mechanisms; however, further pharmacological studies based on cancer models are required. In this study, we investigated the molecular mechanisms underlying the anti-cancer activity of CBC in human pancreatic cancer cells. Through mRNA-seq analysis, the expression levels of many genes involved in cell death pathways were upregulated or downregulated after CBC treatment, and these included ferroptosis-related genes, such as HMOX1. We further confirmed the functional validity of apoptosis and ferroptosis induction after CBC treatment using various molecular assays. In addition, CBC preferentially increased the expression of TRPV1 and CB2. Accordingly, the effects on cell death were reversed after treatment with TRPV1 and CB2 inhibitors, suggesting that receptor expression is necessary for the induction of apoptotic cell death. Finally, we confirmed the consistent regulation of apoptosis, ferroptosis, and endocannabinoid receptors during tumor growth inhibition after CBC treatment using in vivo xenograft models. Therefore, we propose that CBC exhibits pharmacological activity via the integrative modulation of multiple cell death pathways, which can be exploited for pancreatic cancer therapy.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"377"},"PeriodicalIF":7.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0