Chongwu Wang1, Zhaotao Wang2, Chen Chen1, Xiaojun Fu3, Ji Wang4, Xiaowei Fei1, Xiaojing Yan5, Ruxiang Xu1,4,6. 1. The 7th Medical center of Chinese PLA general hospital, Chinese PLA General Hospital Afflicted the Seventh Medical Center, Beijing, China. 2. Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 3. Chinese PLA General Hospital, Medicine School of Chinese PLA, Beijing, China. 4. School of basic medical science, Southern Medicine University, Guangzhou, China. 5. State Key Laboratory of Tree Genetics and Breeding, Chinese Academy of Forestry, Beijing, China. 6. Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Abstract
BACKGROUND AND PURPOSE: As a hallmark of glioblastoma multiforme (GBM), CD44 plays a crucial role in promoting glioblastoma stem cell (GSC) stemness phenotypes and multiple drug resistance. The therapeutic potential of CD44 has been validated by the clinical successes of several CD44 inhibitors, including antibodies and hyaluronan-related drugs. EXPERIMENTAL APPROACH: We used systemsDock software to predict verbascoside as a candidate CD44 inhibitor. Microscale thermophoresis was used to confirm the interaction between CD44 and verbascoside. Four glioblastoma cell lines and a patient-derived glioblastoma cell line were used to test the influences of verbascoside on glioblastoma. CD44-overexpressing and CD44-knockout cell lines were also used. Real-time quantitative PCR and western blot analyses were performed. A xenograft mouse model was used to test verbascoside. KEY RESULTS: Verbascoside bound to CD44 and suppressed its dimerization. By inhibiting CD44 dimerization, verbascoside decreased the release of the CD44 intracellular domain (CD44ICD) and suppressed the expression of CD44 downstream genes. Verbascoside treatment suppressed the stemness phenotypes of cells with high CD44 expression. In a mouse model of glioma, verbascoside treatment highly reduced the growth of intracranial tumours and inhibited CD44ICD release. Both stem cell marker and mesenchymal GBM subtype marker genes were down-regulated in verbascoside-treated mice. CONCLUSION AND IMPLICATIONS: Verbascoside suppressed growth of glioblastoma cells by inhibiting CD44 dimerization. Stem cell-like cell properties and tumour cell growth were also suppressed by verbascoside, both in vitro and in vivo. Verbascoside significantly prolonged survival of xenografted mice.
BACKGROUND AND PURPOSE: As a hallmark of glioblastoma multiforme (GBM), CD44 plays a crucial role in promoting glioblastoma stem cell (GSC) stemness phenotypes and multiple drug resistance. The therapeutic potential of CD44 has been validated by the clinical successes of several CD44 inhibitors, including antibodies and hyaluronan-related drugs. EXPERIMENTAL APPROACH: We used systemsDock software to predict verbascoside as a candidate CD44 inhibitor. Microscale thermophoresis was used to confirm the interaction between CD44 and verbascoside. Four glioblastoma cell lines and a patient-derived glioblastoma cell line were used to test the influences of verbascoside on glioblastoma. CD44-overexpressing and CD44-knockout cell lines were also used. Real-time quantitative PCR and western blot analyses were performed. A xenograft mouse model was used to test verbascoside. KEY RESULTS:Verbascoside bound to CD44 and suppressed its dimerization. By inhibiting CD44 dimerization, verbascoside decreased the release of the CD44 intracellular domain (CD44ICD) and suppressed the expression of CD44 downstream genes. Verbascoside treatment suppressed the stemness phenotypes of cells with high CD44 expression. In a mouse model of glioma, verbascoside treatment highly reduced the growth of intracranial tumours and inhibited CD44ICD release. Both stem cell marker and mesenchymal GBM subtype marker genes were down-regulated in verbascoside-treated mice. CONCLUSION AND IMPLICATIONS: Verbascoside suppressed growth of glioblastoma cells by inhibiting CD44 dimerization. Stem cell-like cell properties and tumour cell growth were also suppressed by verbascoside, both in vitro and in vivo. Verbascoside significantly prolonged survival of xenografted mice.
Authors: R van der Voort; T E Taher; V J Wielenga; M Spaargaren; R Prevo; L Smit; G David; G Hartmann; E Gherardi; S T Pals Journal: J Biol Chem Date: 1999-03-05 Impact factor: 5.157
Authors: Monika Hartmann; Liseth M Parra; Anne Ruschel; Christina Lindner; Helen Morrison; Andreas Herrlich; Peter Herrlich Journal: J Biol Chem Date: 2015-04-29 Impact factor: 5.157
Authors: Sheila K Singh; Ian D Clarke; Mizuhiko Terasaki; Victoria E Bonn; Cynthia Hawkins; Jeremy Squire; Peter B Dirks Journal: Cancer Res Date: 2003-09-15 Impact factor: 12.701
Authors: Daniel V Brown; Paul M Daniel; Giovanna M D'Abaco; Andrew Gogos; Wayne Ng; Andrew P Morokoff; Theo Mantamadiotis Journal: Oncotarget Date: 2015-03-20
Authors: Simon D Harding; Joanna L Sharman; Elena Faccenda; Chris Southan; Adam J Pawson; Sam Ireland; Alasdair J G Gray; Liam Bruce; Stephen P H Alexander; Stephen Anderton; Clare Bryant; Anthony P Davenport; Christian Doerig; Doriano Fabbro; Francesca Levi-Schaffer; Michael Spedding; Jamie A Davies Journal: Nucleic Acids Res Date: 2018-01-04 Impact factor: 16.971
Authors: Gwenda F Vasse; Mehmet Nizamoglu; Irene H Heijink; Marco Schlepütz; Patrick van Rijn; Matthew J Thomas; Janette K Burgess; Barbro N Melgert Journal: J Pathol Date: 2021-03-03 Impact factor: 7.996