Tetrahydrocurcumin Induces Mesenchymal- Epithelial Transition And Suppresses Angiogenesis By Targeting Hif-1 Sigma And Autophagy In Human Osteosarcoma

Human osteosarcoma is considered a malignant tumor with poor prognosis that readily metastasizes. Tetrahydrocurcumin (THC) has been reported to have antitumor activity in numerous tumors. In addition, hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha had a pivotal role in the anti-metastatic effect of THC. Importantly, HIF-1 alpha expression was downregulated by THC by inhibiting Akt/mTOR and p38 MAPK pathways. Moreover, THC exhibited a remarkable inhibitory effect on HIF-1 alpha expression and angiogenesis under hypoxic conditions. Furthermore, THC activated autophagy and induced MET and suppressed angiogenesis in a HIF-1 alpha-related manner. Taken together, our findings suggest that THC suppresses metastasis and invasion and this may be associated with HIF-1 alpha and autophagy, which would potentially provide therapeutic strategies for human osteosarcoma.