Abstract
Human osteosarcoma is considered a malignant tumor with poor prognosis that readily metastasizes. Tetrahydrocurcumin (THC) has been reported to have anti-tumor activity in numerous tumors. In addition, hypoxia-inducible factor-1α (HIF-1α) has been demonstrated to be associated with tumor metastasis by regulating epithelial-mesenchymal transition (EMT). However, the role of THC in osteosarcoma remains uncertain. Therefore, this study aimed to elucidate the potential mechanisms. We found that THC significantly reduced the growth of osteosarcoma cells and suppressed migration and invasion, as tested in a nude mouse lung metastasis model. Additionally, the mesenchymal-epithelial transition (MET) process was facilitated by THC. Mechanistically, our study showed that HIF-1α had a pivotal role in the anti-metastatic effect of THC. Importantly, HIF-1α expression was downregulated by THC by inhibiting Akt/mTOR and p38 MAPK pathways. Moreover, THC exhibited a remarkable inhibitory effect on HIF-1α expression and angiogenesis under hypoxic conditions. Furthermore, THC activated autophagy and induced MET and suppressed angiogenesis in a HIF-1α-related manner. Taken together, our findings suggest that THC suppresses metastasis and invasion and this may be associated with HIF-1α and autophagy, which would potentially provide therapeutic strategies for human osteosarcoma.
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumor among children and adolescents [1,2,3,4]
We found that THC significantly reduced the growth of osteosarcoma cells and suppressed migration and invasion, as tested in a nude mouse lung metastasis model
Our findings suggest that THC suppresses metastasis and invasion and this may be associated with Hypoxia-inducible factor1α (HIF-1α) and autophagy, which would potentially provide therapeutic strategies for human osteosarcoma
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumor among children and adolescents [1,2,3,4]. It is difficult to detect because of the lack of early-stage biomarkers, so that the majority of patients have high-grade malignancy upon diagnosis. The characteristics of advanced OS make them extremely prone to metastasize in the primary stage. The long-term survival rate of patients who have already metastasized is only 10~30% [7]. It is a pressing problem for us to explore the mechanisms of the metastasis of human osteosarcoma and suppress this process to improve survival rates
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