Oridonin inhibits the proliferation of human osteosarcoma cells by suppressing Wnt/β-catenin signaling

Abstract

Abstract. It has been reported that oridonin (ORI) can inhibit proliferation and induce apoptosis in various types of cancer cell lines. However, the exact mechanism for this function remains unclear. In this study, we investigated the proliferation inhibitory effect of ORI on human osteosarcoma (OS) 143B cells and dissected the possible molecular mechanism(s) underlying this effect. We demonstrated that ORI can inhibit proliferation, induce apoptosis and arrest the cell cycle in 143B cells. Using luciferase reporter assay, we found that the Wnt/β-catenin signaling was inhibited in 143B cells by ORI. Accordingly, the total protein levels and nuclear translocation of β-catenin were reduced by ORI treatment. ORI increased glycogen synthase kinase 3β (GSK3β) activity and upregulated Dickkopf-1 (Dkk-1) expression. We found that Dkk-1 overexpression or β-catenin knockdown can potentiate the proliferation inhibitory effect of ORI in 143B cells, while β-catenin overexpression attenuated this effect. Using the xenograft tumor model of human OS, we demonstrated that ORI effectively inhibited the growth of tumors. Histological examination showed that ORI inhibited cancer cell proliferation, decreased the expression of PNCA and β-catenin. Our findings suggest that ORI can inhibit 143B OS cell proliferation by downregulating Wnt/β-catenin signal transduction, which may be mediated by upregulating the Dkk-1 expression and/ or enhancing the function of GSK3β. Therefore, ORI can be potentially used as an effective adjuvant agent for the clinical management of OS.

Artesunate Decreases β-Catenin Expression, Cell Proliferation and Apoptosis Resistance in the MG-63 Human Osteosarcoma Cell Line

“…Moreover, it was reported that concomitant administration of conventional chemotherapeutic agents and artesunate could significantly extend the lifespan of patients with metastatic uveal melanoma [13]. Another study also showed that the Wnt/β-catenin signaling pathway was closely related to the formation, translocation and apoptosis of osteosarcoma [14]. β-catenin, a central molecule in the Wnt/β-catenin pathway, exhibited an abnormal expression pattern in osteosarcoma and was associated with osteosarcoma translocation [15].…”

Inhibitory effects of indirubin‐3′‐monoxime against human osteosarcoma

“…Indirubin‐3′‐monoxime (I3M) has been well characterized as a specific cell‐permeable inhibitor of glycogen synthase kinase‐3β (GSK‐3β), which might be a potent therapeutic target for OS in the recent study . Interestingly, it is reported that I3M prevents the neurotoxicity through the inhibition of GSK‐3β and cytokine production .…”

“…Indirubin-3 0 -monoxime (I3M) has been well characterized as a specific cell-permeable inhibitor of glycogen synthase kinase-3β (GSK-3β), which might be a potent therapeutic target for OS in the recent study. 13,14 Interestingly, it is reported that I3M prevents the neurotoxicity through the inhibition of GSK-3β and cytokine production. 15,16 As one of the synthetic derivatives of indirubin, I3M can regulate multiple signaling pathways such as STAT3 and Notch1 with better solubility and absorption rate.…”

Ursolic acid inhibits proliferation and induces apoptosis by inactivating Wnt/β-catenin signaling in human osteosarcoma cells

“…Luciferase reporter assay. Cells were seeded in T-25 culture flasks and transfected with β-catenin/TCF-4 luciferase reporter (pTOP-luc) 3 µg per flask with Lipofectamine 2000 (Invitrogen) (25,27). The cells were replated into a 24-well plate 16 h after transfection, and then treated with indicated concentrations of UA or DMSO.…”