Cancer Management and Research (May 2020)
Toosendanin Suppresses Glioma Progression Property and Induces Apoptosis by Regulating miR-608/Notch Axis
Abstract
Qiong Wang,1– 3 Zeng Wang,1– 3 Guilan Hou,1– 3 Ping Huang1– 3 1Department of Pharmacy, Institute of Cancer and Basic Medical Sciences of Chinese Academy of Sciences, Hangzhou City, Zhejiang Province 310022, People’s Republic of China; 2Department of Pharmacy, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou City, Zhejiang Province 310022, People’s Republic of China; 3The Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou City, Zhejiang Province 310022, People’s Republic of ChinaCorrespondence: Ping HuangThe Department of Pharmacy, Zhejiang Cancer Hospital, No. 1 Guangji East Road, Gongshu District, Hangzhou City, Zhejiang Province, People’s Republic of China, Tel +86 0571-88122425Email [email protected]: Glioma is one the most common and aggressive primary tumors of adult central nervous system worldwide, which tends to develop dysplasia and metastasis. Recently, toosendanin (TSN) has shown pharmacological effects in several cancers. However, little is known about the underlying mechanism of the effect of TSN on glioma and its relationship between miRNA in glioma.Methods: Cell proliferation, cell cycle, cell apoptosis and cell migration were analyzed by CCK-8 cell viability, flow cytometry, wound scratch healing, transwell and Western blotting assays, respectively, in vitro. The regulation relationships between TSN and miR-608 or between miR-608 and Notch1 (Notch2) were examined using qRT-PCR, dual-luciferase and Western blotting assays. The functional effects of TSN through regulating miR-608 and Notch1 (Notch2) were further examined using a xenograft tumor mouse model in vivo.Results: After TSN concentration was increased from 50 nM, 100 nM to 150 nM, cell proliferation and cell cycle were gradually reduced, and the cell apoptosis rate was increased in U-138MG or U-251MG cells. Wound-healing and transwell assays results showed that cell migration was significantly inhibited in TSN treatment cells (TSN treatment, 50 nM) compared to control cells. Mechanistic studies revealed that TSN up-regulated the expression of microRNA-608 (miR-608), while down-regulated the expression of miR-608’s target, Notch1 and Notch2. Over-expression of Notch1 and Notch2 partly attenuated TSN-induced tumor suppressive function. Moreover, in vivo experiments revealed that TSN treatment led to a significant inhibition of tumor growth, suggesting that it might be a promising drug for the treatment of glioma.Conclusion: In the present study, a novel established functional manner of TSN/miR-608/Notch1 (Notch2) axis was systematically indicated, which might provide prospective intervention ways for glioma therapy.Keywords: glioma, TSN, miR-608, Notch1 and Notch2, tumor growth, metastasis
