Wogonin inhibits multiple myeloma-stimulated angiogenesis via c-Myc/VHL/HIF-1α signaling axis
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Rong Fu1,*, Yan Chen1,*, Xiao-Ping Wang1, Teng An1, Lei Tao1, Yu-Xin Zhou1, Yu-Jie Huang1, Bao-An Chen2, Zhi-Yu Li3, Qi-Dong You4, Qing-Long Guo1, Zhao-Qiu Wu1
1Department of Physiology, State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
2Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing 211189, China
3Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
4Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
*These authors have contributed equally to this work
Qing-Long Guo, e-mail: [email protected]
Zhao-Qiu Wu, e-mail: [email protected]
Keywords: wogonin, angiogenesis, VHL, c-Myc, multiple myeloma
Received: July 26, 2015 Accepted: December 23, 2015 Published: December 30, 2015
Angiogenesis is associated with the progression of multiple myeloma (MM). Wogonin is an active mono-flavonoid with remarkable antitumor activity. However, its impact on MM-stimulated angiogenesis remains largely unknown. Here, we demonstrated that wogonin decreased expression and secretion of pro-angiogenic factors in MM cells via c-Myc/HIF-1α signaling axis, reducing MM-stimulated angiogenesis and MM cell proliferation in vivo. Overexpression of c-Myc in MM cells disrupted the balance between VHL SUMOylation and ubiquitination, and thus inhibited proteasome-mediated HIF-1α degradation. Impaired function of VHL ubiquitination complex in c-Myc-overexpressing cells was fully reversed by wogonin treatment via increasing HIF-1α-VHL interaction and promoting HIF-1α degradation. Collectively, our in vitro and in vivo studies reveal for the first time that wogonin represses MM-stimulated angiogenesis and tumor progression via c-Myc/VHL/HIF-1α signaling axis.
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