Guo Peiyu, Lou Zhenkai, Gong Hongda, Hou Xiaodong, Zhang Chunqiang, Wang Bing, Du Kaili
Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
Mol Med Rep. 2025 Sep;32(3). doi: 10.3892/mmr.2025.13613. Epub 2025 Jul 11.
Osteosarcoma is the most common primary bone cancer, primarily affecting children and young adults. Cancer stem cells (CSCs), a subpopulation presenting stemness, critically influence prognosis and promote recurrence and metastasis. Due to the crucial role of glycogen synthase kinase‑3 beta (GSK‑3β) in maintaining stemness, it is considered as an important target for drug development. The aim of the present study was to evaluate the inhibitory effect of AZD1080, a GSK‑3β inhibitor, on osteosarcoma CSCs. AZD1080 treatment clearly inhibited sphere formation in U2OS and 143B cells and dissociated spheres in CSCs derived from U2OS and 143B; in both processes, stemness markers OCT4 and SOX2 were markedly decreased, without affecting cell proliferation or apoptosis. AZD1080 treatment inhibited phosphorylation of GSK‑3β and its downstream regulated genes, including HEY1, HES1, CyclinD1 and β‑catenin. It was also observed that GSK‑3β activity was critical for the inhibitory effects of AZD1080 treatment on sphere formation and stemness. Moreover, GSK‑3β knockdown inhibited sphere formation and invasion capacity, indicating that AZD1080 exerts inhibitory roles in a GSK‑3β‑dependent manner. Taken together, the results showed AZD1080 as a specific inhibitor of CSC stemness, without cytotoxicity, and indicated it was a promising therapeutic agent that targeted GSK‑3β signaling in osteosarcoma.
骨肉瘤是最常见的原发性骨癌，主要影响儿童和年轻人。癌症干细胞（CSCs）是具有干性的亚群，对预后有至关重要的影响，并促进复发和转移。由于糖原合酶激酶-3β（GSK-3β）在维持干性中起关键作用，它被认为是药物开发的重要靶点。本研究的目的是评估GSK-3β抑制剂AZD1080对骨肉瘤CSCs的抑制作用。AZD1080处理明显抑制了U2OS和143B细胞中的球状体形成，并使源自U2OS和143B的CSCs中的球状体解离；在这两个过程中，干性标志物OCT4和SOX2均明显减少，而不影响细胞增殖或凋亡。AZD1080处理抑制了GSK-3β及其下游调控基因（包括HEY1、HES1、细胞周期蛋白D1和β-连环蛋白）的磷酸化。还观察到GSK-3β活性对于AZD1080处理对球状体形成和干性的抑制作用至关重要。此外，GSK-3β基因敲低抑制了球状体形成和侵袭能力，表明AZD1080以GSK-3β依赖性方式发挥抑制作用。综上所述，结果表明AZD1080是CSC干性的特异性抑制剂，无细胞毒性，并表明它是一种有前景的治疗剂，可靶向骨肉瘤中的GSK-3β信号通路。
