Tetrahydrocurcumin induces mesenchymal-epithelial transition and suppresses angiogenesis by targeting HIF-1α and autophagy in human osteosarcoma
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Yan Zhang1, Ying Liu2,3, Jilong Zou1, Lixin Yan2,3, Wei Du4, Yafeng Zhang3, Hanliang Sun3, Peng Lu5, Shuo Geng1, Rui Gu2,3, Hongyue Zhang2,3 and Zhenggang Bi1
1Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, P.R. China
2Department of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P.R. China
3Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing, Heilongjiang, P.R. China
4School of Pharmacy, Harbin University of Commerce, Harbin, Heilongjiang, P.R. China
5Department of Orthopaedics, Baoquanling Central Hospital, Baoquanling, Heilongjiang, P.R. China
Zhenggang Bi, email: [email protected]
Keywords: human osteosarcoma, tetrahydrocurcumin, mesenchymal-epithelial transition, HIF-1α, autophagy
Received: January 13, 2017 Accepted: July 24, 2017 Published: August 03, 2017
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.
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