Details

Autor(en) / Beteiligte

• Wang, Wei
• Jiang, Shiqing
• Li, Shanshan
• Zhang, Qiao
• Zhu, Xinghao
• Wei, Dandan
• Wang, Yongkun
• Liu, Guangyao

Titel

Tideglusib suppresses stem-cell-like features and progression of osteosarcoma by inhibiting GSK-3[beta]/NOTCH1 signaling

Ist Teil von

• Biochemical and biophysical research communications, 2021-05, Vol.554, p.206

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• Keywords Osteosarcoma; Tideglusib (TID); Stem-cell-like properties; NOTCH1; AKT/GSK-3[beta] Highlights * 1 Tideglusib reduces proliferation and triggers apoptosis in osteosarcoma cells. * 2 Tideglusib inhibits stem-cell-like features in osteosarcoma cells by decreasing NOTCH1 signaling. * 3 Tideglusib suppresses NOTCH1 signal via the blockage of GSK-3[beta] activation. Osteosarcoma is the most common primary bone tumor in children, teenagers and adolescents. Cancer stem cells (CSCs) have the function to self-renew and keep the phenotype of tumor, causing clinical treatment failure. Therefore, developing effective therapies to inhibit osteosarcoma progression is urgently necessary. Glycogen synthase kinase 3[beta] (GSK-3[beta])is highly expressed in osteosarcoma. In the present study, we made an exploration on the anti-tumor effect of tideglusib (TID), a small-molecule inhibitor of GSK-3[beta], and revealed the underlying mechanisms. Here, we found that TID markedly reduced the cell viability of different osteosarcoma cell lines. Cell cycle arrest distributed in G2/M was markedly up-regulated in TID-incubated osteosarcoma cells through enhancing p21 expression levels. Apoptosis was evidently induced in osteosarcoma cells via blocking Caspase-3 activation. Consistently, tumor growth was effectively suppressed in an established murine xenograft model with few toxicity and side effects in vivo. Furthermore, TID markedly repressed stem-cell-like activity in osteosarcoma cells through down-regulating NOTCH1 expression. Notably, rescuing NOTCH1 significantly abolished the role of TID in reducing cell proliferation and sarcosphere-formation. Mechanistically, we found that TID-inhibited NOTCH1 expression was associated with the blockage of AKT/GSK-3[beta] signaling pathway. In summary, we for the first time provided evidence that TID could effectively inhibit osteosarcoma progression through repressing cell proliferation, inducing apoptosis, suppressing stem-cell-like properties via down-regulating AKT/GSK-3[beta]/NOTCH1 signaling pathway. Thus, TID may be a promising therapeutic strategy for osteosarcoma treatment without side effects. Author Affiliation: (a) School of the First Clinical Medical, Henan University of Chinese Medicine, Longzihu University Park, Zhengdong New District, 156 Jinshui East Road, Zhengzhou, 450000, China (b) Department of Oncology, The First Affiliated Hospital of Henan University of Chinese Medicine, 19 Renmin Road, Zhengzhou, 450000, China (c) Biomedical Research and Development Center, Jilin Institute of Biomedicine Ltd.Co, Changchun, 130033, China * Corresponding author. Article History: Received 12 December 2020; Accepted 15 December 2020 Byline: Dandan Wei (a), Xinghao Zhu (a), Shanshan Li (a), Guangyao Liu (c), Yongkun Wang (c), Wei Wang (c), Qiao Zhang (c), Shiqing Jiang [jiangshiqing66@126.com] (b,*)