1. Academic Validation
  2. Tideglusib suppresses stem-cell-like features and progression of osteosarcoma by inhibiting GSK-3β/NOTCH1 signaling

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

  • Biochem Biophys Res Commun. 2021 May 21;554:206-213. doi: 10.1016/j.bbrc.2020.12.055.
Dandan Wei 1 Xinghao Zhu 1 Shanshan Li 1 Guangyao Liu 2 Yongkun Wang 2 Wei Wang 2 Qiao Zhang 2 Shiqing Jiang 3
Affiliations

Affiliations

  • 1 School of the First Clinical Medical, Henan University of Chinese Medicine, Longzihu University Park, Zhengdong New District, 156 Jinshui East Road, Zhengzhou, 450000, China.
  • 2 Biomedical Research and Development Center, Jilin Institute of Biomedicine Ltd.Co, Changchun, 130033, China.
  • 3 Department of Oncology, The First Affiliated Hospital of Henan University of Chinese Medicine, 19 Renmin Road, Zhengzhou, 450000, China. Electronic address: jiangshiqing66@126.com.
Abstract

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 3β (GSK-3β)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-3β, 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-3β 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-3β/NOTCH1 signaling pathway. Thus, TID may be a promising therapeutic strategy for osteosarcoma treatment without side effects.

Keywords

AKT/GSK-3β; NOTCH1; Osteosarcoma; Stem-cell-like properties; Tideglusib (TID).

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