title: Icaritin inhibits JAK/STAT3 signaling and growth of renal cell carcinoma.
abstract: 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.
authors: Genetic Engineering International Cooperation Base of Chinese Ministry of Science and Technology, Key Laboratory of Molecular Biophysics of Chinese Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, Hubei, China.
authors: Shasha
authors: S
authors: Li
authors: Saul J
authors: SJ
authors: Priceman
authors: Hong
authors: H
authors: Xin
authors: Wang
authors: W
authors: Zhang
authors: Jiehui
authors: J
authors: Deng
authors: Yong
authors: Y
authors: Liu
authors: Jiabin
authors: J
authors: Huang
authors: Wenshan
authors: W
authors: Zhu
authors: Mingjie
authors: M
authors: Chen
authors: Wei
authors: W
authors: Hu
authors: Xiaomin
authors: X
authors: Deng
authors: Jian
authors: J
authors: Zhang
authors: Hua
authors: H
authors: Yu
authors: Guangyuan
authors: G
authors: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D053614:Janus Kinase 2; C499403:icaritin