Keming Huang, Qingke Chen, Ling Deng, Qi Zou, Sufang Min
{"title":"Daurisoline通过介导HAKAI蛋白稳定性抑制膀胱癌肿瘤血管生成和上皮间质转化。","authors":"Keming Huang, Qingke Chen, Ling Deng, Qi Zou, Sufang Min","doi":"10.5812/ijpr-129798","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Daurisoline can suppress the development of liver and lung cancers, but its effect on bladder cancer has not been investigated.</p><p><strong>Objectives: </strong>This study probed into the mechanism underlying the effects of daurisoline on angiogenesis and epithelial-mesenchymal transition (EMT) in bladder cancer.</p><p><strong>Methods: </strong>Tissue samples were taken from 40 patients with bladder cancer to analyze the expression of HAKAI and the relationship between HAKAI expression and patient survival. After the gain of function of HAKAI and/or treatment with daurisoline or heat shock protein 90 (HSP90) inhibitor geldanamycin, bladder cancer cells were collected for western blot detection of EMT-related proteins and transwell invasion assay. Tube formation assay assessed the angiogenesis of human umbilical vein endothelial cells (HUVECs) cultured in a conditioned medium of bladder cancer cells. The relationships between daurisoline, HSP90, HAKAI, and E-cadherin (E-cad) were analyzed using drug affinity responsive target stability (DARTS) assay and co-immunoprecipitation (co-IP) method. The effect and action mechanism of daurisoline were validated in nude mice.</p><p><strong>Results: </strong>HAKAI was up-regulated 1.26-fold in bladder cancer tissues (P = 0.004) and correlated with poor prognosis. Daurisoline or geldanamycin inhibited EMT of bladder cancer cells and HUVEC angiogenesis. HAKAI overexpression reversed the suppression by daurisoline or geldanamycin. HAKAI was a client protein of HSP90, which could be directly targeted by daurisoline. HAKAI could target E-cad. Daurisoline also counteracted the promotive effects of overexpressed HAKAI on bladder carcinoma growth in nude mice.</p><p><strong>Conclusions: </strong>Daurisoline suppresses EMT and angiogenesis in bladder cancer by targeting HSP90 and disrupting the stability of HAKAI protein to up-regulate the expression of E-cad.</p>","PeriodicalId":14595,"journal":{"name":"Iranian Journal of Pharmaceutical Research","volume":"21 1","pages":"e129798"},"PeriodicalIF":1.8000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/32/37/ijpr-21-1-129798.PMC10016139.pdf","citationCount":"1","resultStr":"{\"title\":\"Daurisoline Inhibiting Tumor Angiogenesis and Epithelial-Mesenchymal Transition in Bladder Cancer by Mediating HAKAI Protein Stability.\",\"authors\":\"Keming Huang, Qingke Chen, Ling Deng, Qi Zou, Sufang Min\",\"doi\":\"10.5812/ijpr-129798\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Daurisoline can suppress the development of liver and lung cancers, but its effect on bladder cancer has not been investigated.</p><p><strong>Objectives: </strong>This study probed into the mechanism underlying the effects of daurisoline on angiogenesis and epithelial-mesenchymal transition (EMT) in bladder cancer.</p><p><strong>Methods: </strong>Tissue samples were taken from 40 patients with bladder cancer to analyze the expression of HAKAI and the relationship between HAKAI expression and patient survival. After the gain of function of HAKAI and/or treatment with daurisoline or heat shock protein 90 (HSP90) inhibitor geldanamycin, bladder cancer cells were collected for western blot detection of EMT-related proteins and transwell invasion assay. Tube formation assay assessed the angiogenesis of human umbilical vein endothelial cells (HUVECs) cultured in a conditioned medium of bladder cancer cells. The relationships between daurisoline, HSP90, HAKAI, and E-cadherin (E-cad) were analyzed using drug affinity responsive target stability (DARTS) assay and co-immunoprecipitation (co-IP) method. The effect and action mechanism of daurisoline were validated in nude mice.</p><p><strong>Results: </strong>HAKAI was up-regulated 1.26-fold in bladder cancer tissues (P = 0.004) and correlated with poor prognosis. Daurisoline or geldanamycin inhibited EMT of bladder cancer cells and HUVEC angiogenesis. HAKAI overexpression reversed the suppression by daurisoline or geldanamycin. HAKAI was a client protein of HSP90, which could be directly targeted by daurisoline. HAKAI could target E-cad. Daurisoline also counteracted the promotive effects of overexpressed HAKAI on bladder carcinoma growth in nude mice.</p><p><strong>Conclusions: </strong>Daurisoline suppresses EMT and angiogenesis in bladder cancer by targeting HSP90 and disrupting the stability of HAKAI protein to up-regulate the expression of E-cad.</p>\",\"PeriodicalId\":14595,\"journal\":{\"name\":\"Iranian Journal of Pharmaceutical Research\",\"volume\":\"21 1\",\"pages\":\"e129798\"},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2022-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/32/37/ijpr-21-1-129798.PMC10016139.pdf\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Iranian Journal of Pharmaceutical Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.5812/ijpr-129798\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Iranian Journal of Pharmaceutical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5812/ijpr-129798","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Daurisoline Inhibiting Tumor Angiogenesis and Epithelial-Mesenchymal Transition in Bladder Cancer by Mediating HAKAI Protein Stability.
Background: Daurisoline can suppress the development of liver and lung cancers, but its effect on bladder cancer has not been investigated.
Objectives: This study probed into the mechanism underlying the effects of daurisoline on angiogenesis and epithelial-mesenchymal transition (EMT) in bladder cancer.
Methods: Tissue samples were taken from 40 patients with bladder cancer to analyze the expression of HAKAI and the relationship between HAKAI expression and patient survival. After the gain of function of HAKAI and/or treatment with daurisoline or heat shock protein 90 (HSP90) inhibitor geldanamycin, bladder cancer cells were collected for western blot detection of EMT-related proteins and transwell invasion assay. Tube formation assay assessed the angiogenesis of human umbilical vein endothelial cells (HUVECs) cultured in a conditioned medium of bladder cancer cells. The relationships between daurisoline, HSP90, HAKAI, and E-cadherin (E-cad) were analyzed using drug affinity responsive target stability (DARTS) assay and co-immunoprecipitation (co-IP) method. The effect and action mechanism of daurisoline were validated in nude mice.
Results: HAKAI was up-regulated 1.26-fold in bladder cancer tissues (P = 0.004) and correlated with poor prognosis. Daurisoline or geldanamycin inhibited EMT of bladder cancer cells and HUVEC angiogenesis. HAKAI overexpression reversed the suppression by daurisoline or geldanamycin. HAKAI was a client protein of HSP90, which could be directly targeted by daurisoline. HAKAI could target E-cad. Daurisoline also counteracted the promotive effects of overexpressed HAKAI on bladder carcinoma growth in nude mice.
Conclusions: Daurisoline suppresses EMT and angiogenesis in bladder cancer by targeting HSP90 and disrupting the stability of HAKAI protein to up-regulate the expression of E-cad.
期刊介绍：
The Iranian Journal of Pharmaceutical Research (IJPR) is a peer-reviewed multi-disciplinary pharmaceutical publication, scheduled to appear quarterly and serve as a means for scientific information exchange in the international pharmaceutical forum. Specific scientific topics of interest to the journal include, but are not limited to: pharmaceutics, industrial pharmacy, pharmacognosy, toxicology, medicinal chemistry, novel analytical methods for drug characterization, computational and modeling approaches to drug design, bio-medical experience, clinical investigation, rational drug prescribing, pharmacoeconomics, biotechnology, nanotechnology, biopharmaceutics and physical pharmacy.
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