Caudatin Inhibits the Proliferation, Invasion, and Glycolysis of Osteosarcoma Cells via the Wnt/β- Catenin Pathway

Abstract

Background. Caudatin is a steroidal glycoside with reported anticancer activity in a variety of studies. Nevertheless, the role and mechanisms of caudatin in osteosarcoma (OS) remain unclear. In this study, we explored the potential anticancer effects of caudatin in OS cells and investigated the underlying mechanisms. Methods. Both the CCK8 proliferation assay and flow cytometry were employed to evaluate cell proliferation and apoptosis. A transwell assay was applied to determine cell invasion ability. Besides, glycolytic capacity was examined by measuring glucose consumption, lactic acid production, as well as ATP production. A western blot was utilized to assess the protein levels of β-catenin, CyclinD 1, C-myc, HK2 (Hexokinase 2), LDHA (lactate dehydrogenase), as well as epithelial-mesenchymal transition (EMT)-related markers. The inhibitory effect of caudatin on tumor growth was investigated using a xenograft tumorigenesis model. Results. Caudatin restrained cellular glycolysis, suppressed cell proliferation and invasion by reducing HK2 and LDHA expression and regulating the Wnt/β-Catenin signaling pathway. Caudatin treatment caused the upregulation of E-cadherin and suppressed N-cadherin expression. Further, caudatin treatment impaired cell viability, invasion ability, and intracellular glycolysis level but induced apoptosis. The administration of BML 284 reversed the inhibitory effects of caudatin. Moreover, caudatin suppressed the tumorigenesis of OS cells in the xenograft model of nude mice. Conclusions. Our study revealed the anticancer effects of caudatin, including proliferation inhibition, cell invasion suppression, and glycolysis impairment. These effects seem to be executed through targeting the Wnt/β-Catenin signaling pathway. These data indicate that caudatin may be formulated as a potential therapeutic for osteosarcoma.

USP22 as a key regulator of glycolysis pathway in osteosarcoma: insights from bioinformatics and experimental approaches

“…Currently, many anticancer drugs or genes have been found to improve tumor progression in osteosarcoma and other cancers by reversing the “Warburg effect” and suppressing glycolysis. For example, Caudatin, a naturally occurring steroidal glycoside with anticancer activities, was found to inhibit osteosarcoma cell proliferation and invasion by suppressing glycolysis ( Zhang et al, 2022 ). Deng et al (2022) showed Ubiquitin-like protein FAT10 could promote osteosarcoma glycolysis and growth.…”

Reprogramming of glucose metabolism: Metabolic alterations in the progression of osteosarcoma

“…Therefore, it is speculated that apigenin inhibits the Warburg effect and cell proliferation of OS cells by inhibiting the PI3K/Akt/mTOR signaling pathway. Research [136] has found that caudatin inhibits cellular glycolysis by reducing the expression of HK2 and LDHA, possibly by downregulating the expression of β-Catenin, Cyclin D1, and C-myc to inhibit the Wnt/β-catenin signaling pathway, thereby affecting the glycolysis process, and ultimately achieving the goal of inhibiting the proliferation and metastasis of OS cells [136] . Resveratrol inhibited the proliferation and glycolysis of OS cells by inhibiting the activity and downstream gene expression of Wnt/β-catenin signaling pathway and enhancing the expression of Cx43 and e-cadherin genes [137] .…”