International Journal of Biological Sciences最新文献

{"title":"Ugonin P mitigates osteolytic bone metastasis by suppressing MDK via upregulating miR-223-3p expression.","authors":"Yat-Yin Law, Haritha Rengamanar, Chih-Ying Wu, Chih-Chuang Liaw, Shubham Suresh Ghule, Yu-Ying Wu, Kuan-Ying Lai, Le Huynh Hoai Thuong, Trung-Loc Ho, Athena Yanjen Lin, Yi-Chin Fong, Chun-Hao Tsai, Chih-Hsin Tang","doi":"10.7150/ijbs.111356","DOIUrl":"10.7150/ijbs.111356","url":null,"abstract":"<p><p>Bone metastasis is a significant complication in advanced-stage cancers, especially breast and lung malignancies, profoundly influencing prognosis and quality of life. Osteolytic bone metastasis contains multiple interactions between cancer cells and the bone microenvironment, driving osteoclast-mediated bone resorption and deterioration while releasing growth factors that promote tumor progression. Current treatments, including surgery, radiation, and chemotherapy, often result in severe side effects, highlighting the need for effective, targeted therapies. Ugonin P, a natural compound derived from <i>Helminthostachys zeylanica</i>, known for its anti-inflammatory and anticancer properties. However, the effects of Ugonin P on osteolytic bone metastasis remain unclear. Our findings demonstrate that Ugonin P inhibits both RANKL-induced and lung and breast cancer-induced osteoclast formation. Bioinformatics analysis revealed that Midkine (MDK), a heparin-binding growth factor known to promote migration, is highly elevated in breast and lung cancer patients and is related with osteoclast formation. We further showed that MDK is involved in cancer-promoted osteoclastogenesis and that Ugonin P suppresses this process by upregulating miR-223-3p expression. Importantly, Ugonin P effectively blocks lung and breast cancer-facilitated osteolytic bone metastasis <i>in vivo</i>. These findings highlight Ugonin P as a promising therapeutic strategy for treating osteolytic bone metastasis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3740-3754"},"PeriodicalIF":8.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301960","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}

{"title":"ITLN1 exacerbates Crohn's colitis by driving ZBP1-dependent PANoptosis in intestinal epithelial cells through antagonizing TRIM8-mediated CAPN2 ubiquitination.","authors":"Jie Zhao, Yujiang Li, Pu Ying, Yan Zhou, Ziwei Xu, Dongmei Wang, Honggang Wang, Liming Tang","doi":"10.7150/ijbs.105550","DOIUrl":"10.7150/ijbs.105550","url":null,"abstract":"<p><p><b>Background:</b> This study aimed to investigate the mechanisms by which PANoptosis of intestinal epithelial cells (IECs) promotes Crohn's disease (CD) progression. <b>Methods:</b> Single-cell RNA sequencing (scRNA-seq) was performed on inflamed and uninflamed colon tissues from patients with CD. The biological functions of intelectin-1 (ITLN1) in inflammation and PANoptosis were verified through <i>in vitro</i> experiments. The molecular mechanisms underlying its biological functions were examined using co-immunoprecipitation (Co-IP) combined with mass spectrometry (MS) and RNA-seq and further validated with rescue experiments. Additionally, the <i>in vivo</i> function of ITLN1 regulation on inflammation, PANoptosis, and the intestinal mucosal barrier was explored in interleukin-10 knockout (IL-10 KO) colitis model mice. <b>Results:</b> ITLN1 was significantly overexpressed in IECs from inflamed colon tissues and specifically associated with CD-related inflammatory markers. RNA-seq and <i>in vitro</i> experiments indicated that ITLN1 promotes inflammation, PANoptosis, and impaired tight junctions. Co-IP and MS analyses revealed that ITLN1 can bind to the PANoptosis-promoting protein calpain-2 (CAPN2) and enhance its stability. The E3 ubiquitin ligase, a tripartite motif containing 8 (TRIM8), directly interacts with CAPN2 and mediates its ubiquitination degradation. ITLN1 can bind to TRIM8, and its impact on inflammation and Z-DNA binding protein 1 (ZBP1)-induced PANoptosis can be antagonized by CAPN2. These <i>in vivo</i> studies indicated that short hairpin-ITLN1 improves colonic inflammation and intestinal barrier function in IL-10 KO mice. <b>Conclusion:</b> We identified the ITLN1-TRIM8-CAPN2 axis that drives IEC PANoptosis in CD progression. Pharmacological inhibition of ITLN1 significantly mitigated epithelial damage and colitis both <i>in vivo</i> and <i>in vitro</i>, establishing ITLN1-targeted therapies and PANoptosis modulation as viable clinical strategies for CD treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3705-3725"},"PeriodicalIF":8.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302018","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}

{"title":"Regulatory Action of Calcium and Calcium Channels in Pain Pathways.","authors":"Yan Zhang, John Shannonhouse, Hyeonwi Son, Joon Tae Park, Yu Shin Kim","doi":"10.7150/ijbs.110504","DOIUrl":"10.7150/ijbs.110504","url":null,"abstract":"<p><p>Calcium ions (Ca²⁺) and Ca²⁺ channels are pivotal in the regulation of pain pathways and serve as key regulators of neuronal excitability and neurotransmitter release. We review the different types of Ca²⁺ channels involved in pain processing, including voltage-gated Ca²⁺ channels (VGCCs), such as L-, N-, P/Q-, and T-type channels. Each subtype is intricately involved in different aspects of pain perception, from acute pain signaling to the development and maintenance of chronic pain states. In addition, the roles of transient receptor potential (TRP) channels, particularly TRPV1 and TRPA1, are discussed in the context of their contribution to chronic pain. Advances in Ca²⁺ imaging techniques, particularly through genetically encoded Ca²⁺ indicators (GECIs), such as GCaMPs, have provided unprecedented insight into the dynamic role of Ca²⁺ channels in pain pathways. These efforts have deepened our understanding of Ca²⁺ channels and suggest novel therapeutic targets for more effective pain management strategies within Ca²⁺ channels.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3726-3739"},"PeriodicalIF":8.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301948","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}

{"title":"Mechanistic role of metal-responsive transcription factor-1 (MTF1) in cadmium-induced prostate carcinogenesis.","authors":"Balaji Chandrasekaran, Bhawna Tyagi, Ashish Tyagi, Vaibhav Shukla, Mollie Schatz, Thulasidharan Nair Devanarayanan, Neha Tyagi, Chendil Damodaran","doi":"10.7150/ijbs.110174","DOIUrl":"10.7150/ijbs.110174","url":null,"abstract":"<p><p>Our previous report emphasized that chronic exposure to cadmium (10 µM) over one year led to the transformation of benign prostatic hyperplasia (BPH1) cells into malignancy through the ZIC2 signaling pathway (cerebellar zinc pathway). However, the upstream mechanisms that trigger this transformation have yet to be fully elucidated. The present study suggests that cadmium exposure induces metal regulatory element-binding transcription factor-1 (MTF1), which activates ZIC2 in BPH1 cells. Interestingly, knocking out ZIC2 expression did not affect MTF1 levels, indicating that MTF1 acts upstream of the ZIC2 signaling pathway. To further investigate the MTF-1/ZIC2 relationship, we overexpressed MTF-1 in untransformed BPH1 cells leading to the induction of ZIC2 along with other stem cell markers, such as ALDH1A1, Nanog, and CD44. This overexpression also facilitated spheroid formation. Conversely, silencing MTF1 expression in transformed cells inhibited spheroid formation and also reduced survival rate. It diminished the expression of stem cell and epithelial-to-mesenchymal transition markers and tumor growth in nude mice. Transcriptomic analysis of MTF1 silenced xenograft tumors confirmed these findings. Using CRISPR-Cas9 to knock out ZIC2 also prevented tumor formation in nude mice. These results emphasize the critical role of MTF1 in the oncogenic process and its involvement in the ZIC2-mediated transformation associated with Cd-induced malignant changes.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3614-3630"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301939","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}

{"title":"MNX1-AS1 suppresses chemosensitivity by activating the PI3K/AKT pathway in breast cancer.","authors":"You Shuai, Zhonghua Ma, Jian Yue, Chunxiao Li, Jie Ju, Xue Wang, Haili Qian, Peng Yuan","doi":"10.7150/ijbs.104483","DOIUrl":"10.7150/ijbs.104483","url":null,"abstract":"<p><p>Long noncoding RNAs (lncRNAs) critically regulate tumorigenesis and chemosensitivity. Despite the pivotal role of lncRNAs in breast cancer (BC), their specific functions and underlying mechanism, particularly in the context of drug resistance, remain largely unexplored. We discovered that MNX1-AS1 is significantly elevated in BC and contributes to paclitaxel resistance through the PI3K/AKT pathway. Moreover, elevated MNX1-AS1 expression exhibits close association with unfavourable prognosis in BC. Mechanistically, MNX1-AS1 interacts with YBX1, preventing its SMURF2-mediated ubiquitination and subsequent degradation, thereby increasing YBX1 protein levels. Upregulated YBX1 transcriptionally activates the expression of ITGA6 by binding to its promoter in the nucleus. Furthermore, MNX1-AS1 binds to IGF2BP2, promoting the stability of ITGA6 mRNA in an m6A-dependent manner within the cytoplasm. MNX1-AS1 increases ITGA6 expression at transcriptional and post-transcriptional levels, thereby activating the PI3K/AKT pathway. Notably, lipid nanoparticles were implicated to effectively deliver MNX1-AS1 siRNA to tumor-bearing mice, resulting in significant antitumor effects. These findings underscore the role of MNX1-AS1 in activating the ITGA6/PI3K/AKT pathway, which facilitates tumor progression and induces chemoresistance in BC. Targeting MNX1-AS1 may represent a promosing therapeutic strategy to enhance chemotherapy efficacy in BC patients.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3689-3704"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301942","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}

{"title":"Radio-chemotherapy and metformin selectively modulate the heterogeneous landscape of glioma with ribosome biogenesis, long non coding RNA and immune-escape markers as major player.","authors":"Silvia Valtorta, Silvia Granata, Stefano de Pretis, Gloria Bertoli, Serena Redaelli, Valeria Berno, Antonello E Spinelli, Santo Diprima, Paolo Rainone, Angela Coliva, Sergio Todde, Giovanni Marfia, Stefania Navone, Manuela Caroli, Angela Bentivegna, Nadia Di Muzio, Rosa Maria Moresco","doi":"10.7150/ijbs.103194","DOIUrl":"10.7150/ijbs.103194","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a short survival time after standard therapy administration including radiotherapy (RT) associated with temozolomide (TMZ). Here, we investigated the effects of radiochemotherapy in association with metformin (MET), a drug targeting cell metabolism on a syngeneic GBM mouse model using Positron Emission Tomography imaging with [¹⁸F]FLT and [¹⁸F]VC701 and single-cell RNA-sequencing analysis. The addition of drugs to RT significantly increased survival and [¹⁸F]FLT showed an early predictive response of combined therapy. We identified the presence of heterogeneous tumor populations with different treatment sensitivity and a complex immune evasive microenvironment. Tumor cells surviving to treatments showed immune response, among the main differentially modulated biological functions and a potential role of long non-coding RNAs (lncRNAs) in treatment resistance. Association with TMZ or TMZ plus MET reduced the pro-tumor phenotype of immune reaction acting more on myeloid cells the first and on lymphocytes the latter. Off note, MET add-on counteracted the immune-evasive phenotype particularly of T cells suggesting a potential role of MET also in adopted immunity.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3527-3554"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301947","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}

{"title":"Integrative Single-Cell and Spatial Transcriptomics Analysis Reveals ECM-remodeling Cancer-associated Fibroblast-Derived POSTN as a Key Mediator in Pancreatic Ductal Adenocarcinoma Progression.","authors":"Yifan Wu, Shuquan Li, Hao Yu, Sha Zhang, Liang Yan, Xiaoya Guan, Wei Xu, Zhen Wang, Ang Lv, Xiuyun Tian, Chunyi Hao, Jianhui Wu","doi":"10.7150/ijbs.108618","DOIUrl":"10.7150/ijbs.108618","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) presents significant clinical challenges owing to its dense stroma and complex tumor microenvironment (TME). In this study, large-scale single-cell transcriptomics and spatial transcriptomics (ST) were integrated to dissect the heterogeneity of fibroblasts and their crosstalk with epithelial cells, with a focus on key ligand-receptor interactions. Eight distinct fibroblast subpopulations were identified, among which extracellular matrix (ECM)-remodeling fibroblasts were particularly enriched in tumor tissues and associated with poor prognosis. ECM-remodeling fibroblasts were located at the terminal stage of the fibroblast pseudotime trajectory, and SOX11 was identified as a key transcription factor in this subpopulation. Further analyses revealed that ECM-remodeling fibroblasts can interact with epithelial cells through the POSTN-ITGAV/ITGB5 ligand-receptor axis, a critical pathway that promotes tumor progression. Clinical analyses demonstrated a strong correlation between POSTN expression and poor prognosis in patients with PDAC. Mechanistically, POSTN interacts with integrin ITGAV/ITGB5 on tumor cells, activating the PI3K/AKT/β-catenin pathway and promoting epithelial-mesenchymal transition (EMT) phenotype. Pharmacological inhibition of the POSTN-integrin axis partially reversed these malignant traits, highlighting its potential as a therapeutic target. This study provides new insights into fibroblast heterogeneity and its role in PDAC progression, emphasizing the POSTN-ITGAV/ITGB5 axis as a promising target for therapeutic interventions.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3573-3596"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302017","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}

{"title":"TrkC protects against osteoarthritis progression by maintaining articular cartilage homeostasis.","authors":"Yongyun Chang, Keyu Kong, Hua Qiao, Minghao Jin, Xinru Wu, Wenxuan Fan, Jingwei Zhang, Yansong Qi, Yongsheng Xu, An Qin, Zanjing Zhai, Huiwu Li","doi":"10.7150/ijbs.108832","DOIUrl":"10.7150/ijbs.108832","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a degenerative disease with a series of metabolic changes accompanied by chondrocyte apoptosis. Chondrocytes express multiple receptors for neurotrophin, however, the role of neurotrophin receptor in chondrocyte metabolism remains unelucidated. Here, we first clarify the role of neurotrophin 3 (NT3) and its receptor tropomyosin receptor kinase C (TrkC) of chondrocytes in OA pathogenesis, using inducible TrkC-deficient mice (TrkC^fl/fl; Col2a1-CreER^T2 mice). Our findings show that TrkC levels are decreased in the chondrocytes and cartilage of patients with OA and OA-model mice. Chondrocyte-specific TrkC deficiency aggravates cartilage destruction during OA development. However, intra-articular TrkC-overexpressing adeno-associated virus (AAV) injection delays experimental OA progression. TrkC deficiency leads to decreased anabolic and increased catabolic activities in chondrocytes and stimulates chondrocyte apoptosis, thereby accelerating OA progression. Whereas TrkC overexpression rescues the imbalance between extracellular matrix synthesis and degradation and chondrocyte apoptosis through PI3K/Akt signaling. NT3, a multifunctional protein with high affinity for TrkC, effectively protects against cartilage degeneration in OA models <i>in vitro</i> and <i>in vivo</i> and relieves pain sensitivity in mice with OA. Our results indicate that TrkC is crucial for maintaining cartilage homeostasis and OA progression. Targeting TrkC with NT3 could be a novel strategy for OA treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3597-3613"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301950","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}

{"title":"Identification of a Novel Small Molecule STING Agonist Reshaping the Immunomicroenvironment of Pancreatic Ductal Adenocarcinoma.","authors":"Pengyi Liu, Minmin Shi, Yang Liu, Yihao Liu, Jiayu Lin, Shuyu Zhai, Yizhi Cao, Dongjie Chen, Yongsheng Jiang, Chenghong Peng, Lei Zhang, Chunyong Ding, Lingxi Jiang, Baiyong Shen","doi":"10.7150/ijbs.107837","DOIUrl":"10.7150/ijbs.107837","url":null,"abstract":"<p><p><b>Background:</b> Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor response to immunotherapy. The immunosuppressive tumor microenvironment, characterized by a dense extracellular matrix, and immunosuppressive cells, plays a crucial role in this resistance. The cGAS-STING pathway, traditionally recognized for antiviral defense, has emerged as a potential target for cancer immunotherapy due to its ability to activate both innate and adaptive immune responses. <b>Methods:</b> A novel small-molecule STING agonist, D166, was synthesized by incorporating deuterium into the structure, leading to improved stability and activation of the STING pathway. The effects of D166 were evaluated using human pancreatic tumor organoids, mouse pancreatic tumor models, and various <i>in vitro</i> and <i>in vivo</i> assays, including flow cytometry, RNA sequencing, ELISA and western blotting. And an organoid-immune cells co-culture system was established for further investigate the effects on immune cells. <b>Results:</b> D166 demonstrated significant anti-tumor activity, effectively activating the cGAS-STING pathway in a time- and dose-dependent manner. D166 inhibited the progression of pancreatic tumor organoids and mouse pancreatic tumors, reshaping the tumor immune microenvironment. The drug enhanced T cell activation, promoted macrophage polarization toward the M1 phenotype, and increased the infiltration of immune cells. Additionally, D166 acted as a sensitizer for anti-PD-1 therapy, significantly improving therapeutic efficacy in combination treatments. <b>Conclusion:</b> D166 is a novel and stable STING agonist that inhibits pancreatic tumor progression by activating the cGAS-STING pathway and remodeling the tumor immune microenvironment. Its combination with anti-PD-1 antibodies offers a promising strategy for overcoming the immunosuppressive barriers in pancreatic cancer, providing new therapeutic insights and directions.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3555-3572"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302016","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}

{"title":"PARP inhibitor augments anti-tumor efficacy of DNMT inhibitor by inducing senescence in cholangiocarcinoma.","authors":"Peili Wang, Rong Xiao, Jianfeng Chen, Peiyong Guan, Hong Lee Heng, Lizhen Liu, Yali Wang, Xian Zeng, Guixiang Zhong, Jing Hao, Jiuping Gao, Jason Yongsheng Chan, Simona Dima, Choon Kiat Ong, Bin Tean Teh, Mei Li, Jing Han Hong, Jing Tan","doi":"10.7150/ijbs.110947","DOIUrl":"10.7150/ijbs.110947","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is an aggressive, heterogeneous malignancy with limited effective treatment options. One of the key epigenetic dysregulations in CCA is aberrant DNA hypermethylation, suggesting that targeted DNA methylation is a promising therapeutic strategy for this disease. However, there is still limited information on how effective DNA demethylating agents are in the treatment of CCA in the clinical setting, and further studies are urgently needed to evaluate their potential benefits. Here, we established four patient-derived CCA cell lines and demonstrated that the DNA methyltransferase (DMNT) inhibitors decitabine and azacitidine had minimal effects on inhibiting CCA proliferation. A combinatorial drug screen identified PARP inhibitors as sensitizers that synergistically enhanced the antitumor effects of decitabine. The combination of DNMT inhibitors and PARP inhibitors therapeutically inhibited the growth of CCA cancers in multiple <i>in vitro</i> cancer cell lines and organoid models, as well as <i>in vivo</i> cell line-derived xenografts, patient-derived xenograft models, and CCA in mice induced by hydrodynamic tail vein injection. Mechanistically, transcriptomic profiling analysis showed that combination treatment activated the inflammatory signaling pathway and suppressed the cell cycle-related pathways in CCA. In addition, the combination synergistically induced DNA damage and cellular senescence of CCA cancer cells. Together, our study provides a preclinical proof-of-concept for the use of DNMT inhibitors in combination with PARP inhibitors as a novel therapeutic strategy and potentially optimizes current clinical practice in the treatment of CCA.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3649-3665"},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301944","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}