Tideglusib suppresses stem-cell-like features and progression of osteosarcoma by inhibiting GSK-3ß/NOTCH1 signaling.
Biochem Biophys Res Commun
; 554: 206-213, 2021 05 21.
Article
en En
| MEDLINE
| ID: mdl-33813076
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 3ß (GSK-3ß)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-3ß, 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-3ß 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-3ß/NOTCH1 signaling pathway. Thus, TID may be a promising therapeutic strategy for osteosarcoma treatment without side effects.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Células Madre
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Tiadiazoles
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Neoplasias Óseas
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Osteosarcoma
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Receptor Notch1
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Glucógeno Sintasa Quinasa 3 beta
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2021
Tipo del documento:
Article
País de afiliación:
China