Icaritin Inhibits JAK/STAT3 Signaling and Growth of Renal Cell Carcinoma

作者：Shasha Li, Saul J. Priceman, Hong Xin, Wang Zhang, Jiehui Deng, Yong Liu, Jiabin Huang, Wenshan Zhu, Mingjie Chen, Wei Hu, Xiaomin Deng, Jian Zhang, Hua Yu, Guangyuan He · 发表于：PLoS ONE · 年份：2013 · DOI：10.1371/journal.pone.0081657 · 被引用次数：119 · 研究领域：Medicinal Plant Pharmacodynamics Research、Cytokine Signaling Pathways and Interactions、Cancer-related molecular mechanisms research

Signal transducer and activator of transcription-3 (STAT3) is critical for cancer progression by regulating tumor cell survival, proliferation, and angiogenesis. Herein, we investigated the regulation of STAT3 activation and the therapeutic effects of Icaritin, a prenyl flavonoid derivative from Epimedium Genus, in renal cell carcinoma (RCC). Icaritin showed significant anti-tumor activity in the human and mouse RCC cell lines, 786-O and Renca, respectively. Icaritin inhibited both constitutive and IL-6-induced phospho-STAT3 (STAT3(Y705)) and reduced the level of STAT3-regulated proteins Bcl-xL, Mcl-1, Survivin, and CyclinD1 in a dose-dependent manner. Icaritin also inhibited activation of Janus-activated kinase-2 (JAK2), while it showed minimal effects on the activation of other key signaling pathways, including AKT and MAPK. Expression of the constitutively active form of STAT3 blocked Icaritin-induced apoptosis, while siRNA directed against STAT3 potentiated apoptosis. Finally, Icaritin significantly blunted RCC tumor growth in vivo, reduced STAT3 activation, and inhibited Bcl-xL and Cyclin E, as well as VEGF expression in tumors, which was associated with reduced tumor angiogenesis. Overall, these results suggest that Icaritin strongly inhibits STAT3 activation and is a potentially effective therapeutic option for the treatment of renal cell carcinoma.