Cancer Biology & Therapy最新文献

{"title":"Effect of extracellular vesicle ZNF280B derived from lung cancer stem cells on lung cancer progression.","authors":"Qixia Guo, Jiayan Lu, Hui Zhao, Ding Zhou, Hua Liu","doi":"10.1080/15384047.2025.2450849","DOIUrl":"10.1080/15384047.2025.2450849","url":null,"abstract":"<p><strong>Objective: </strong>The purpose of this research was to investigate the role of extracellular vesicles derived from lung cancer stem cells (lung CSCs-EVs) in lung cancer and to explore their potential mechanisms.</p><p><strong>Methods: </strong>Lung CSCs were first isolated and verified using flow cytometry and RT-qPCR assays. Lung CSCs-EVs were extracted through ultracentrifugation and further characterized using transmission electron microscopy and Western blotting. The interaction between lung CSCs-EVs and lung cancer cells was observed through PKH67 staining. Subsequently, we analyzed the differentially expressed genes in lung CSCs using bioinformatics data analysis and evaluated the prognostic value of ZNF280B in lung cancer with the Kaplan-Meier Plotter. RT-qPCR was utilized to assess the mRNA expression levels of these genes, while Western blotting was used to evaluate the protein expression levels of ZNF280B and P53. Next, CCK-8 and colony formation assays were conducted to assess the effects of lung CSCs-EVs and ZNF280B on cancer cell proliferation, migration (via wound healing assay), and invasion (using transwell assay). Additionally, subcutaneous tumor-bearing experiments in nude mice were performed to evaluate the roles of lung CSCs-EVs in lung cancer progression <i>in vivo</i>.</p><p><strong>Results: </strong>The results indicated that lung CSCs-EVs accelerated the progression of lung cancer. Mechanistically, these lung CSCs-EVs transferred ZNF280B into cancer cells, leading to the inhibition of P53 expression.</p><p><strong>Conclusions: </strong>In summary, the manuscript first describes the molecular mechanism by which lung CSCs-EVs promote pro-cancer functions in lung cancer through the ZNF280B/P53 axis.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2450849"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NVP-2, in combination with Orlistat, represents a promising therapeutic strategy for acute myeloid leukemia.","authors":"Qing Zhu, Jia Cheng, Yuqing Gao, Zimu Zhang, Jian Pan, Xin Su, Danhong Fei, Linbo Cai, Juanjuan Yu, Yanling Chen, Wanyan Jiao, Di Wu, Xiaolu Li, Peifang Xiao","doi":"10.1080/15384047.2025.2450859","DOIUrl":"10.1080/15384047.2025.2450859","url":null,"abstract":"<p><p>Cell cycle dysregulation and the corresponding metabolic reprogramming play significant roles in tumor development and progression. CDK9, a kinase that regulates gene transcription and cell cycle, also induces oncogene transcription and abnormal cell cycle in AML cells. The function of CDK9 for gene regulation in AML cells requires further exploration. In this study, we knocked down the CDK9 to investigate its effects on the growth and survival of AML cells. Through RNA-seq analysis, we identified that in U937 cells CDK9 regulates numerous genes involved in proliferation and apoptosis, including mTOR, SREBF1, and Bcl-2. Furthermore, our results demonstrated that both CDK9 and FASN are crucial for the proliferation and survival of Kasumi-1 and U937 cells. Mechanistically, MCL1, c-Myc, and Akt/mTOR/SREBF1 may be critical factors and pathways in the combined therapy of NVP-2 and Orlistat. In summary, our study revealed that CDK9 and FASN are vital for maintaining AML cell survival and proliferation. Treatment with NVP-2 and Orlistat may be a promising clinical candidate for patients with AML.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2450859"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>PCK2</i> promotes invasion and epithelial-to-mesenchymal transition in triple-negative breast cancer by promoting TGF-β/SMAD3 signaling through inhibiting TRIM67-mediated SMAD3 ubiquitination.","authors":"Tsung-Ming Chang, Wei-Yu Fang, Hui-Ping Hsu, Pei-Yi Chu, Shih Sheng Jiang, Kuo-Wei Huang, Wen-Chun Hung, Hui-You Lin, Hui-Jen Tsai","doi":"10.1080/15384047.2025.2478670","DOIUrl":"10.1080/15384047.2025.2478670","url":null,"abstract":"<p><p><i>PCK2</i>, which encodes mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), is upregulated in various cancers. We demonstrated high expression of PEPCK-M in approximately half of triple-negative breast cancers (TNBCs) previously. TNBC is associated with an aggressive phenotype and a high metastasis rate. In this study, we investigated the role of <i>PCK2</i> in TNBC. <i>PCK2</i> knockdown suppressed proliferation and mTOR signaling in TNBC cells. In addition, cell invasion/migration ability and the expression of epithelial-to-mesenchymal transition (EMT) markers were positively correlated with <i>PCK2</i> expression in TNBC cells via regulation of transforming growth factor-β (TGF-β)/SMAD3 signaling. <i>SMAD3</i> was positively regulated by <i>PCK2</i> in TNBC cells. Knockdown of <i>SMAD3</i> in <i>PCK2</i>-overexpressing TNBC cells reduced the expression levels of EMT markers, Snail and Slug, and suppressed cell invasion/migration. In addition, <i>PCK2</i> knockdown attenuated the stimulatory effect of TGF-β on SMAD3 phosphorylation in TNBC cells. PEPCK-M promotes the protein and mRNA expression of SMAD3 via competitive binding to tripartite motif-containing 67 (TRIM67), an E3 ubiquitin ligase, to reduce SMAD3 ubiquitination, which leads to promoting nuclear translocation of SMAD3 and autoregulation of SMAD3 transcription. Moreover, high <i>PCK2</i> mRNA expression was significantly associated with poor survival in TNBC patients. In conclusion, our study revealed for the first time that <i>PCK2</i> activates TGF-β/SMAD3 signaling by regulating the expression and phosphorylation of SMAD3 by inhibiting TRIM67-mediated SMAD3 ubiquitination and promoting the stimulatory effect of TGF-β to promote TNBC invasion. The regulatory effect of <i>PCK2</i> on mTOR and TGF-β/SMAD3 signaling suggests that <i>PCK2</i> is a potential therapeutic target for suppressing TNBC progression.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2478670"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pan-cancer analysis of MARCH8: molecular characteristics, clinical relevance, and immuno-oncology features.","authors":"Zihan Quan, Songqing Fan, Hongmei Zheng, Yue Ning, Yang Yang","doi":"10.1080/15384047.2025.2458773","DOIUrl":"10.1080/15384047.2025.2458773","url":null,"abstract":"<p><p>Membrane-associated RING-CH8 (MARCH8) is a member of the recently discovered MARCH family of ubiquitin ligases. MARCH8 has been shown to participate in immune responses. However, the role of MARCH8 in prognosis and immunology in human cancers remains largely unknown. The expression of MARCH8 protein was detected via immunohistochemistry in non-small cell lung cancer (NSCLC) and non-cancerous lung tissues. The study investigated the role of MARCH8 in tumor immunity through pan-cancer analysis of multiple databases. MARCH8 genetic alternations and expression were explored with the cBioPortal, GTEx, and TCGA databases. We investigated the role of MARCH8 expression in clinical relevance, prognosis, tumor immune microenvironment, immune checkpoint (ICP) with a series of bioinformatics tools and methods, such as TISIDB database, ESTIMATE, and CIBERSORT method. MARCH8 expression showed cancer-specific dysregulation and was associated with the prognosis of patients in various cancers. MARCH8 was related to the tumor microenvironment and participated in tumor immune regulation. Furthermore, low expression of MARCH8 was associated with poor prognosis and might serve as an independent prognostic biomarker for NSCLC patients. The comprehensive pan-cancer analysis revealed the potential of MARCH8 in tumor-targeted therapy, and suggested MARCH8 as a promising prognostic and immunological pan-cancer biomarker.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2458773"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfatase 2 inhibition sensitizes triple-negative breast cancer cells to paclitaxel through augmentation of extracellular ATP.","authors":"Jasmine M Manouchehri, Jharna Datta, Lynn M Marcho, Daniel Stover, Ramesh K Ganju, Bhuvaneswari Ramaswamy, William E Carson, Arjun Mittra, Xiaoli Zhang, Patrick M Schnell, Yu Yue, Mark P Rubinstein, Mathew A Cherian","doi":"10.1080/15384047.2025.2483989","DOIUrl":"10.1080/15384047.2025.2483989","url":null,"abstract":"<p><p>The highest incidence and cancer-related mortality rate among women worldwide is due to breast cancer. Triple-negative breast cancers (TNBC) are associated with more inferior outcomes than other breast cancers because of their progressive nature and the deficit in available therapies. Therefore, there is a need for new therapeutic approaches. Our lab determined that chemotherapy induces the release of extracellular adenosine triphosphate (eATP), and, hence, augments TNBC cells' response to chemotherapy. Despite this, eATP concentrations are restricted by a variety of extracellular ATPases. We propose that, as an ATPase inhibitor, heparan sulfate (HS) would augment eATP concentrations and TNBC vulnerability induced by chemotherapy. Sulfatase 2 (SULF2) removes sulfate from HS, the functional group essential for ATPase inhibition. Consequently, we propose that TNBC cell death and eATP release induced by chemotherapy would be intensified by SULF2 inhibitors. We examined eATP and cell viability in paclitaxel-treated TNBC and nontumorigenic immortal mammary epithelial MCF-10A cells in the presence of OKN-007, a selective SULF2 inhibitor, and/or heparan sodium sulfate. Furthermore, sulfatase 1 (SULF1) and SULF2 protein expressions were ascertained. We found that the expression of SULF2 was greater in TNBC cell lines when compared to MCF-10A cells. The release of eATP and loss of TNBC cell viability induced by chemotherapy was enhanced by OKN-007. The co-treatment of chemotherapy and OKN-007 also attenuated cancer-initiating cells. This data implies that the combination of SULF2 inhibitors with chemotherapy augments eATP and decreases cell viability of TNBC greater than chemotherapy alone.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2483989"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the molecular and genetic role of obesity in breast cancer pathogenesis.","authors":"Sandeep Mallya, Varsha Gangadhar, Sophia Evangeline Aldrin, Meghana Acharya, Shama Prasada Kabekkodu, Kiran Kumar Kolathur, Sanjiban Chakrabarty","doi":"10.1080/15384047.2025.2501345","DOIUrl":"10.1080/15384047.2025.2501345","url":null,"abstract":"<p><p>The epidemic of obesity is a growing concern and is one of the major risk factors for several chronic diseases, including several types of cancers. The correlation of breast cancer with obesity has been extensively studied and involves an interplay of hormonal, metabolic, and genetic factors explored in this review. Inflammation and hormone dysregulation play an important role in promoting a protumorigenic environment through adipose tissue, which is involved in energy storage and functions as an endocrine organ. As a result, various cytokines, primarily proinflammatory in nature, are released, resulting in low-grade inflammation promoting tumor growth. Additionally, obese conditions also induce imbalances in hormones, particularly estrogen and insulin, both of which drive carcinogenesis. Genetic components such as single nucleotide polymorphisms also play critical roles in modulating the correlation between obesity and breast cancer. This review provides a comprehensive overview of various mechanisms underlying obesity and breast cancer incidence and progression.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2501345"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing ZIC5 suppresses glycolysis and promotes disulfidptosis in lung adenocarcinoma cells.","authors":"Cimei Zeng, Denggao Huang, Lei Wang, Haimei Liang, Ximiao Ma","doi":"10.1080/15384047.2025.2501780","DOIUrl":"https://doi.org/10.1080/15384047.2025.2501780","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to explore the effects of silencing Zic family member 5 (ZIC5) on glucose metabolism and disulfidptosis in lung adenocarcinoma (LUAD) cells.</p><p><strong>Methods: </strong>Data from The Cancer Genome Atlas (TCGA) was used to analyze ZIC5 expression in LUAD and its association with patient outcomes. ZIC5 was silenced in A549 and H1299 cells using siRNA. The expression of ZIC5 mRNA and protein was assessed by qRT-PCR and Western blot. Cell proliferation was evaluated through CCK-8 and 5-ethynyl-2'-deoxyuridine (EdU) assays, while glucose uptake, lactate production, and ATP levels were measured to assess energy metabolism. Seahorse XF analysis was used to evaluate extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Disulfidptosis was assessed through NADP⁺/NADPH ratio, glutathione (GSH) content, GSSG/GSH ratio, and immunofluorescence staining.</p><p><strong>Results: </strong>ZIC5 is highly expressed in LUAD and is associated with poor patient prognosis. Silencing ZIC5 significantly reduced its mRNA and protein levels in A549 and H1299 cells, markedly inhibited cell proliferation, and led to significant decreases in glucose uptake, lactate production, ATP levels, ECAR, and OCR. Additionally, silencing ZIC5 resulted in an increased NADP⁺/NADPH ratio, decreased GSH levels, and a reduced GSSG/GSH ratio, alongside classic disulfidptosis features.</p><p><strong>Conclusion: </strong>ZIC5 plays a crucial role in promoting LUAD cell proliferation and energy metabolism while inhibiting disulfidptosis. Silencing ZIC5 markedly suppresses these processes, indicating its potential as a therapeutic target in LUAD.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2501780"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RSK4 promotes the metastasis of clear cell renal cell carcinoma by activating RUNX1-mediated angiogenesis.","authors":"Jing Ma, Yanru Yang, Kaijing Wang, Jin Liu, Junyi Feng, Gongcheng Wang, Shuangping Guo, Linni Fan","doi":"10.1080/15384047.2025.2452025","DOIUrl":"10.1080/15384047.2025.2452025","url":null,"abstract":"<p><p>Ribosomal S6 protein kinase 4 (RSK4), a member of the serine‒threonine kinase family, plays a vital role in the Ras‒MAPK pathway. This kinase is responsible for managing several cellular activities, including cell growth, proliferation, survival, and mobility. In this study, we observed higher RSK4 protein expression in clear cell renal cell carcinoma (ccRCC) than in normal kidney tissue, and the overexpression of RSK4 might predict poor outcomes for ccRCC patients. Notably, renal cell carcinoma (RCC) is rich in blood vessels; therefore, this study aimed to explore the biological function of RSK4 in ccRCC progression and its specific regulatory mechanism. We analyzed changes in the expression of target genes through transcriptomic and proteomic assessments. We also conducted tube formation assays and VEGF ELISAs to understand the role of RSK4 in angiogenesis. Additionally, we evaluated the regulatory effect of RUNX1 on EPHA2 transcription using a luciferase reporter gene assay and observed that the effect of RUNX1 on activating EPHA2 transcription was negated after the binding site was mutated. Our findings suggested that RSK4 enhanced tube formation by stimulating VEGF secretion. Concurrently, in vivo experiments confirmed that RSK4 expedited RCC metastasis and angiogenesis. This evidence indicates that RSK4 may serve as a new prognostic marker and play a vital role in RCC metastasis.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2452025"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of TTYH3 by lncRNA LUCAT1 through interacting with ALYREF facilitates the metastasis in non-small cell lung cancer.","authors":"Fang Fang, Mei Zhao, Jinming Meng, Jiaqi He, Chunlei Yang, Changhong Wang, Jiaxiao Wang, Sheng Xie, Xiaowei Jin, Wei Shi","doi":"10.1080/15384047.2025.2464966","DOIUrl":"10.1080/15384047.2025.2464966","url":null,"abstract":"<p><p>Metastasis is the predominant culprit of cancer-associated mortality in non-small cell lung cancer (NSCLC). Tweety homolog 3 (TTYH3) reportedly functions vitally in the development of diverse cancers, including NSCLC; nevertheless, its role in NSCLC metastasis remains ambiguous. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were initially employed to detect TTYH3 expression in NSCLC and normal lung epithelial cells. Subsequently, A549 and NCI-H1650 cells were chosen as NSCLC models in vitro and transfected with short hairpin RNAs (sh-TTYH3, sh-LUCAT1, and sh-ALYREF) or overexpression plasmids (oe-ALYREF and oe-TTYH3). Transwell assays were used for migrative and invasive tests. Epithelial mesenchymal transformation (EMT)-related proteins (E-cadherin, N-cadherin, Vimentin, and Snail) were measured by western blot. A mouse lung metastasis model was built to define the function of TTYH3 in NSCLC metastasis, followed by hematoxylin-eosin staining. RNA pull-down, RNA immunoprecipitation, qRT-PCR, western blot, and actinomycin D assays were adopted to determine the relationships among LUCAT1, ALYREF, and TTYH3. TTYH3 was highly expressed in NSCLC cells relative to normal lung cells. Functionally, TTYH3 knockdown restrained NSCLC migration, invasion, EMT, and metastasis. Mechanistic experiments demonstrated that LUCAT1 bound to ALYREF. After LUCAT1 knockdown, TTYH3 expression and mRNA stability were reduced, which was reversed by ALYREF overexpression. Furthermore, ALYREF overexpression counteracted the inhibitory effects of LUCAT1 knockdown on NSCLC cell migration, invasion, and EMT. TTYH3 overexpression eliminated the suppressive functions of ALYREF downregulation in NSCLC progression. LUCAT1 promotes TTYH3 expression via interacting with ALYREF, thereby facilitating NSCLC migration, invasion, and EMT.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2464966"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the IKZF1/BCL-2 axis as a novel therapeutic strategy for treating acute T-cell lymphoblastic leukemia.","authors":"Juan Li, Chunmei Ye, Hui Li, Jun Li","doi":"10.1080/15384047.2025.2457777","DOIUrl":"10.1080/15384047.2025.2457777","url":null,"abstract":"<p><strong>Objectives: </strong>Acute T-cell lymphoblastic leukemia (T-ALL) is a severe hematologic malignancy with limited treatment options and poor long-term survival. This study explores the role of IKZF1 in regulating BCL-2 expression in T-ALL.</p><p><strong>Methods: </strong>CUT&Tag and CUT&Run assays were employed to assess IKZF1 binding to the BCL-2 promoter. IKZF1 overexpression and knockdown experiments were performed in T-ALL cell lines. The effects of CX-4945 and venetoclax, alone and in combination, were evaluated in vitro and in vivo T-ALL models.</p><p><strong>Results: </strong>CUT&Tag sequencing identified IKZF1 binding to the BCL-2 promoter, establishing it as a transcriptional repressor. Functional assays demonstrated that IKZF1 overexpression reduced BCL-2 mRNA levels and increased repressive histone marks at the BCL-2 promoter, while IKZF1 knockdown led to elevated BCL-2 expression. CX-4945, a CK2 inhibitor, could reduced BCL-2 levels in T-ALL cells. Notably, knockdown of IKZF1 partially rescued the CX-4945-induced repression of BCL-2. These results underscore the CK2-IKZF1 signaling axis as a key regulator of BCL-2 expression. In vitro, CX-4945 enhanced the cytotoxicity of venetoclax, with the combination showing significant synergistic effects and increased apoptosis in T-ALL cell lines. In vivo studies with cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models demonstrated that CX-4945 and venetoclax combined therapy provided superior therapeutic efficacy, reducing tumor burden and prolonging survival compared to single-agent treatments.</p><p><strong>Conclusions: </strong>IKZF1 represses BCL-2 in T-ALL, and targeting the CK2-IKZF1 axis with CX-4945 and venetoclax offers a promising therapeutic strategy, showing enhanced efficacy and potential as a novel treatment approach for T-ALL.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2457777"},"PeriodicalIF":4.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}