Tetrahydrocurcumin induces mesenchymal-epithelial transition and suppresses angiogenesis by targeting HIF-1α and autophagy in human osteosarcoma

Abstract

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-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 antimetastatic 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.

Anti‐angiogenesis triggers exosomes release from endothelial cells to promote tumor vasculogenesis

“…Tumor vasculogenesis includes both VM and endothelial vasculogenesis [5,65]. Previous studies suggest that induction of autophagy might be associated with tumor vasculogenesis in some tumors [66,67] but the formation of VM is independent of VEGF‐driven angiogenesis through the autophagy pathway and activation of Flk1 [67,68]. Our findings indicate that inhibition of autophagy by 3‐MA abolished miR‐9‐induced EC angiogenesis, similar to that following vandetanib treatment.…”

Sinomenine Hydrochloride Inhibits the Metastasis of Human Glioblastoma Cells by Suppressing the Expression of Matrix Metalloproteinase-2/-9 and Reversing the Endogenous and Exogenous Epithelial-Mesenchymal Transition

“…Moreover, the use of different model systems (mouse or different human cell lines) may explain the obvious variation in results [ 15 , 47 , 48 , 49 , 50 ]. Nevertheless, autophagy activation has been shown to impair the metastasis of tumor cells by reversing EMT [ 47 , 51 , 52 , 53 ]. EMT is a process by which cells switch their epithelial properties to a mesenchymal and invasive phenotype, enabling them to invade the ECM [ 54 , 55 ].…”

Cyclohexanone curcumin analogs inhibit the progression of castration‐resistant prostate cancer in vitro and in vivo

“…Although the lung metastasis area of the curcumin‐treated group was slightly lower than the analog 2A‐treated group, it was determined to be not significant. Curcumin is rapidly metabolized to dihydrocurcumin and tetrahydrocurcumin, which have anti‐metastasis properties . Metabolism of curcumin might be the one situation that promotes its anti‐metastasis activity.…”

“…Curcumin is rapidly metabolized to dihydrocurcumin and tetrahydrocurcumin, which have antimetastasis properties. [22][23][24] Metabolism of curcumin might be the one situation that promotes its anti-metastasis activity. Therefore, metabolism of analog 2A and the biological activities of analog 2A…”