Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.H...Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.展开更多
利用分子力场分析法(comparative molecular field analysis,CoMFA)、比较分子相似性指数法(comparative molecular similarity indices analysis,CoMSIA)和分子对接方法对一系列喹唑啉类TNKS抑制剂进行三维定量构效关系研究。构建的CoM...利用分子力场分析法(comparative molecular field analysis,CoMFA)、比较分子相似性指数法(comparative molecular similarity indices analysis,CoMSIA)和分子对接方法对一系列喹唑啉类TNKS抑制剂进行三维定量构效关系研究。构建的CoMFA(q^(2)=0.578,r^(2)=0.998,r^(2)_(pred)=0.815)和CoMSIA(q^(2)=0.624,r^(2)=0.929,r^(2)_(pred)=0.747)模型具有良好的鲁棒性、预测能力和机制可解释能力。分子对接实验结果表明:Ser1221和Gly1185是影响这些抑制剂活性的主要氨基酸。研究对设计新型TNKS抑制剂具有参考意义。展开更多
Tankyrase1(TNKS1)plays an essential role in cancer progression by regulating telomere length.The study aimed to determine expression of TNKS1 and its regulation in colorectal cancer(CRC)in 20 samples from Saudi patien...Tankyrase1(TNKS1)plays an essential role in cancer progression by regulating telomere length.The study aimed to determine expression of TNKS1 and its regulation in colorectal cancer(CRC)in 20 samples from Saudi patients.mRNA expression of TNKS1 in CRC and paired normal tissues was measured by qRT-PCR.Epigenetic modification of TNKS1 promoter was determined by methylation-specific PCR while somatic mutation was analyzed by Sanger sequencing in exon 10 of the gene.All cancerous and normal tissues expressed TNKS1,but level of expression in CRC tissues was significantly associated with tumor stage though no other parameters;age,gender,and tumor location,showed any correlation.Expression of TNKS1 was markedly higher in earlier(I,II)than in later(Ⅲ,Ⅳ)stages of CRC development.Both cancerous and healthy tissues had unmethylated promoters.Sanger sequencing of exon 10 masked any somatic mutation in the samples.Our findings suggest that up-regulation of TNKS1 was inversely correlated with cancer progression in CRC,indicating that TNKS1 participates in the initiation of CRC by stabilizing telomere length in the first phase of cancer progression.Mechanisms other than TNKS1 might play a role in malignant tumor progression and telomere maintenance in the late stages of CRC.展开更多
基金This study was financially supported by the National Key Research and Development Program of China(2022YFC2804100,2021YFF0502400,2022YFC2804300)National Natural Science Foundation of China(82073713,22137006,82104033,82173730,81903499,32070070,82160669)Innovative research team of highlevel local universities in Shanghai(SHSMU-ZDCX20212702,China).We thank Dr.Juncheng Su from Shanghai Jiao-Tong University School of Medicine(Shanghai,China)for providing the LoVo and COLO 320DM cell lines.
文摘Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
文摘利用分子力场分析法(comparative molecular field analysis,CoMFA)、比较分子相似性指数法(comparative molecular similarity indices analysis,CoMSIA)和分子对接方法对一系列喹唑啉类TNKS抑制剂进行三维定量构效关系研究。构建的CoMFA(q^(2)=0.578,r^(2)=0.998,r^(2)_(pred)=0.815)和CoMSIA(q^(2)=0.624,r^(2)=0.929,r^(2)_(pred)=0.747)模型具有良好的鲁棒性、预测能力和机制可解释能力。分子对接实验结果表明:Ser1221和Gly1185是影响这些抑制剂活性的主要氨基酸。研究对设计新型TNKS抑制剂具有参考意义。
基金funded by King Abdulaziz City for Science and Technology(KACST),grant number(1-17-01-001-0056).
文摘Tankyrase1(TNKS1)plays an essential role in cancer progression by regulating telomere length.The study aimed to determine expression of TNKS1 and its regulation in colorectal cancer(CRC)in 20 samples from Saudi patients.mRNA expression of TNKS1 in CRC and paired normal tissues was measured by qRT-PCR.Epigenetic modification of TNKS1 promoter was determined by methylation-specific PCR while somatic mutation was analyzed by Sanger sequencing in exon 10 of the gene.All cancerous and normal tissues expressed TNKS1,but level of expression in CRC tissues was significantly associated with tumor stage though no other parameters;age,gender,and tumor location,showed any correlation.Expression of TNKS1 was markedly higher in earlier(I,II)than in later(Ⅲ,Ⅳ)stages of CRC development.Both cancerous and healthy tissues had unmethylated promoters.Sanger sequencing of exon 10 masked any somatic mutation in the samples.Our findings suggest that up-regulation of TNKS1 was inversely correlated with cancer progression in CRC,indicating that TNKS1 participates in the initiation of CRC by stabilizing telomere length in the first phase of cancer progression.Mechanisms other than TNKS1 might play a role in malignant tumor progression and telomere maintenance in the late stages of CRC.
