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

// Yan Zhang 1 , Ying Liu 2, 3 , Jilong Zou 1 , Lixin Yan 2, 3 , Wei Du 4 , Yafeng Zhang 3 , Hanliang Sun 3 , Peng Lu 5 , Shuo Geng 1 , Rui Gu 2, 3 , Hongyue Zhang 2, 3 and Zhenggang Bi 1 1 Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, P.R. China 2 Department of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P.R. China 3 Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing, Heilongjiang, P.R. China 4 School of Pharmacy, Harbin University of Commerce, Harbin, Heilongjiang, P.R. China 5 Department of Orthopaedics, Baoquanling Central Hospital, Baoquanling, Heilongjiang, P.R. China Correspondence to: Zhenggang Bi, email: hydbizhenggang@163.com Keywords: human osteosarcoma, tetrahydrocurcumin, mesenchymal-epithelial transition, HIF-1α, autophagy Received: January 13, 2017      Accepted: July 24, 2017      Published: August 03, 2017 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.