Cancer gene therapy最新文献

{"title":"Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery.","authors":"Danda Chapagai, Klaus Strebhardt, Michael D Wyatt, Campbell McInnes","doi":"10.1038/s41417-025-00907-7","DOIUrl":"https://doi.org/10.1038/s41417-025-00907-7","url":null,"abstract":"<p><p>Polo Like Kinase 1 (PLK1), a key regulator of mitosis whose overexpression is often associated with poor survival rates in cancer, continues to be widely investigated as an oncology drug target with clinical trials evaluating second and third generation inhibitors. In addition to the conserved N-terminal kinase domain (KD), a unique characteristic of the Polo-Like kinase family is the C-terminal polo-box domain (PBD). The PBD contains a phosphopeptide binding site that recognizes substrates primed by other kinases and furthermore is responsible for subcellular localization of PLK1 to specific sites in the nucleus including centrosomes and kinetochores. Another role of the PBD is its regulatory ability through domain-domain interactions with the KD to maintain an autoinhibited state of PLK1. Insights into post translational modifications and the PBD - KD domain-domain association have been obtained and show that key events in PLK1 regulation include phosphosubstrate binding, T210 phosphorylation and engagement with the Bora protein. These can induce an open and active conformation where the domain-domain inhibitory interactions no longer dominate. Further regulatory events recently described include the interchange between monomeric and dimeric forms, which can also serve to inhibit or activate PLK1 during the cell cycle. Different oligomeric forms of PLK1, existing as homodimers and heterodimers with PLK2, have been identified and likely play context dependent roles. This review provides an overview of recent information describing structural and mechanistic insights into inhibition of PLK1 and the temporal and spatial requirements of its activation and regulation. It also covers recent insights into the conformational regulation of other members of the Polo-Like kinase family. The implications of the conformational regulation of PLK1 with respect to cell cycle function and drug discovery are significant and are therefore discussed in detail.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Old versus new: upstream and downstream of promyelocytic leukemia zinc finger protein.","authors":"Kai Wang, Deyu Guo, Shijie Sun, Kang Tian, Hongchang Shen, Jiajun Du","doi":"10.1038/s41417-025-00912-w","DOIUrl":"https://doi.org/10.1038/s41417-025-00912-w","url":null,"abstract":"<p><p>Promyelocytic leukemia zinc finger (PLZF) is a member of the zinc finger protein family and has been extensively studied due to its crucial role in influencing stem cell self-renewal, spermatogenesis, T cell differentiation, tumorigenesis, and development. Its function is regulated by multidimensional and multilevel regulation. Recent studies have explored the mechanism of action of PLZF in different diseases and related treatment strategies. This study aimed to summarize the regulatory mechanisms underlying PLZF expression and function, and update the latest PLZF regulatory targets and interacting molecules. We also summarized the mechanism by which PLZF promoted the transcriptional activation of target genes, besides its role as a transcriptional repressor. This study revealed a more detailed upstream and downstream regulatory mechanism of PLZF, providing directions for future research.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4.","authors":"Tianzhen Hu, Chengyun Pan, Tianzhuo Zhang, Ming Ni, Weili Wang, Siyu Zhang, Ying Chen, Jishi Wang, Qin Fang","doi":"10.1038/s41417-025-00913-9","DOIUrl":"https://doi.org/10.1038/s41417-025-00913-9","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioblastoma-associated macrophages in glioblastoma: from their function and mechanism to therapeutic advances.","authors":"Yuqin Zhang, Hanxing He, Xin Fu, Ganzhi Liu, Huiying Wang, Wen Zhong, Xia Xu, Bo Chen, Lin Mei","doi":"10.1038/s41417-025-00905-9","DOIUrl":"https://doi.org/10.1038/s41417-025-00905-9","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults and has high mortality rates worldwide. GBM progression, treatment, and prognosis are influenced by the tumor microenvironment (TME), which includes immune, stromal, and tumor cells. Among them, glioblastoma-associated macrophages (GAMs) act as key regulators of GBM pathobiology. GAMs exhibit remarkable plasticity, as they can exhibit both protumor and antitumor effects. However, their function is determined by polarization and the TME. In this review, we provide a comprehensive overview of the current understanding of the biology of GAMs in GBM, including their origins, phenotypic diversity, and functional roles. We discuss the intricate crosstalk between GAMs and tumor cells, as well as other immune and stromal components, and highlight the mechanisms underlying GAM-mediated tumor progression, invasion, angiogenesis, and immune system evasion. Furthermore, we explore the therapeutic implications of targeting GAMs in GBM and discuss emerging strategies aimed at reprogramming GAMs toward an antitumorigenic phenotype or selectively depleting protumorigenic subsets. The final aim is to develop innovative therapeutic approaches that disrupt GBMs. By leveraging our increased understanding of GAM biology, we lay the foundation for transformative advances in GBM treatment to improve patient prognosis.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability.","authors":"María Trinidad Moreno-Montilla, Sergio Pedraza-Arevalo, Ana Martínez-López, Ricardo Blázquez-Encinas, Víctor García-Vioque, Lidia Rodríguez-Ortiz, Francisca Valenzuela-Molina, Blanca Rufián-Andújar, Melissa Granados-Rodríguez, Rosa Ortega-Salas, Emilia Alors-Pérez, Mari C Vázquez-Borrego, Antonio Romero-Ruiz, Justo P Castaño, Álvaro Arjona-Sánchez, Alejandro Ibáñez-Costa","doi":"10.1038/s41417-025-00911-x","DOIUrl":"https://doi.org/10.1038/s41417-025-00911-x","url":null,"abstract":"<p><p>Pseudomyxoma peritonei (PMP) is a rare neoplasm coursing with uncontrollable mucus accumulation, with a high relapse rate. RNA biology processes have emerged as new players in cancer development and progression, nevertheless their role in PMP remains unknown. In this study, we aimed to examine RNA-regulatory machineries in PMP and their potential contribution to this disease progression. We analyzed 62 splicing-related genes, 27 RNA exosome and 21 nonsense-mediated decay genes, in a cohort of 29 patients using a microfluidic array, comparing tumor and control/reference tissues, together with external RNA-seq and proteomic data. Our results revealed a profound dysregulation of key components, which correlated to relevant clinical parameters and enabled to distinguish between tumor and control tissues. In vitro splicing inhibition using Pladienolide-B, as well as the modulation of specific splicing factors, reduced aggressiveness parameters, enhanced the effect of clinically used drugs, and revealed a strong correlation between dysregulated genes and key cancer-related genes. This inhibition also affected mucin secretion and mucin variants production. Collectively, our findings provide the first evidence for dysregulation of the genes of pivotal RNA-regulatory processes in PMP, implying that these targetable mechanisms may be functionally altered and play a role in the disease. Hence, a thorough understanding of its RNA biology could aid in the discovery of new clinically actionable vulnerabilities in this rare disease.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM).","authors":"Filipa Martins, Renata Arada, Hélio Barros, Paulo Matos, José Ramalho, Valentín Ceña, Vasco D B Bonifácio, Luís G Gonçalves, Jacinta Serpa","doi":"10.1038/s41417-025-00906-8","DOIUrl":"https://doi.org/10.1038/s41417-025-00906-8","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PURE_G4) surface functionalized with lactate (LA) (PURE_G4-LA₂₄), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PURE_G4-LA₂₄) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PURE_G4-LA₂₄ and TMZ@PURE_G4-LA₂₄ induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PURE_G4-LA₁₂ (PURE_G4-LA₁₂-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells. PURE_G4-LA₁₂-anti-GLS1-siRNA dendriplexes cross the blood-brain barrier (BBB) and impair glioblastoma (GBM) metabolism. The BBB is formed by a thin monolayer of specialized brain microvascular endothelial cells joined together by tight junctions that selectively control the passage of substances from the blood to the brain. It is a major obstacle in the treatment of GBM, since many chemotherapeutic drugs are unable to penetrate the brain. Therefore, we developed a strategy to overcome this obstacle: a lactate-coated polyurea dendrimer generation 4 (PURE_G4) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PURE_G4-LA₁₂ are nanoparticles functionalized with lactate (LA) to target MCT1, a lactate transporter highly expressed by GBM cells. Moreover, a complex of this nanoparticle with anti-GLS1 (glutaminase) siRNA (PURE_G4-LA₁₂-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PURE_G4-LA₂₄ loaded with SeChry led to BBB disruption.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The role of tumor-derived exosomal LncRNA in tumor metastasis.","authors":"Zhile Yu, Jiali Fu, Vanya Mantareva, Ivica Blažević, Yusong Wu, Dianchang Wen, Tungalag Battulga, Yuqing Wang, Jianye Zhang","doi":"10.1038/s41417-025-00909-5","DOIUrl":"https://doi.org/10.1038/s41417-025-00909-5","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Long non-coding RNA MEG3 promotes the proliferation of glioma cells through targeting Wnt/β-catenin signal pathway.","authors":"X Gong, M Huang","doi":"10.1038/s41417-025-00908-6","DOIUrl":"https://doi.org/10.1038/s41417-025-00908-6","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ARL6IP5 in cancers: bidirectional function and therapeutic value.","authors":"Zenan Hu, Hanxun Yue, Liang Qiao","doi":"10.1038/s41417-025-00903-x","DOIUrl":"https://doi.org/10.1038/s41417-025-00903-x","url":null,"abstract":"<p><p>ARL6IP5 (ADP-ribosylation-like factor 6 interacting protein 5) plays an important role in a variety of physiological or pathological processes, including in cancers. However, the biological roles of ARL6IP5 in cancers are controversial. In this mini-review, we summarized the current understanding on the role of ARL6IP5 in cancers, particularly in the progression of chronic hepatitis virus-related hepatocellular carcinoma, as well as the potential values of ARL6IP5 in cancer therapy.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The activated tyrosine kinase ACK1 by multiple receptor tyrosine kinases promotes proliferation and invasion of mesothelioma via regulation of PI3K/AKT/mTOR and RAF/MAPK signaling pathways.","authors":"Yue Qiao, Shuihao Zhu, Zhenni Liu, Natalia Kelley, Zhencang Zheng, Jonathan A Fletcher, Wen-Bin Ou","doi":"10.1038/s41417-025-00904-w","DOIUrl":"https://doi.org/10.1038/s41417-025-00904-w","url":null,"abstract":"<p><p>Activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and AXL has been described in subsets of mesothelioma, suggesting that tyrosine kinases (TKs) might represent therapeutic targets in this chemotherapy resistant and highly lethal cancer. In the present study, activated TKs were identified in mesothelioma cells by phosphotyrosine immunoaffinity purification and tandem mass spectrometry, and biological functions were evaluated. The results showed that non-RTK activated-CDC42 kinase 1 (ACK1) was highly expressed and activated in 8 of 9 mesothelioma cell lines and 15 of 18 mesothelioma biopsies, but not in normal mesothelial cells. This ACK1 activation was in turn driven by the collective activation of EGFR, MET, and AXL. ACK1 inactivation by either a small molecule inhibitor (AIM-100) or RNAi had anti-proliferative, anti-migration, and pro-apoptotic effects in four mesothelioma cultures due to G1 arrest and xenograft model. These responses resulted from inhibition of the PI3K/AKT/mTOR and RAF/MAPK pathways, inhibition of cyclin A and cyclin D1, and up-regulation of cell cycle checkpoints TP53, CDKN1A (p21), and CDKN1B (p27). Combination treatment with AIM-100, cisplatin (CIS), and pemetrexed (PEM) had greater impact on mesothelioma response (apoptosis, proliferation arrest, and inhibition of migration and invasion) compared to administering only one or two of these agents. The current findings identify ACK1 as a single downstream target that can be inhibited to stymie these multiple receptor tyrosine kinase (EGFR, MET, and AXL) oncogenic programs in mesothelioma, and highlight that ACK1 inhibition, potentially in combination with PEM and CIS, warrants evaluation as a therapeutic strategy in mesothelioma.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}