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: 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
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e81657 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24324713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Flavonoids
• STAT3 Transcription Factor
• Vascular Endothelial Growth Factor A
• Janus Kinase 2
• icaritin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Renal Cell (blood supply, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Flavonoids (pharmacology, therapeutic use)
• Humans
• Janus Kinase 2 (metabolism)
• Kidney Neoplasms (blood supply, enzymology, pathology)
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic (drug therapy, enzymology, pathology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)