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.
PLoS One. 2013 Dec 6;8(12):e81657. doi: 10.1371/journal.pone.0081657. eCollection 2013.
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.
信号转导子和转录激活因子 3（STAT3）通过调节肿瘤细胞的存活、增殖和血管生成，对癌症的进展至关重要。在此，我们研究了 STAT3 激活的调节以及淫羊藿素（一种来自淫羊藿属的类异戊二烯黄酮衍生物）在肾细胞癌（RCC）中的治疗作用。淫羊藿素在人源和鼠源 RCC 细胞系 786-O 和 Renca 中均显示出显著的抗肿瘤活性。淫羊藿素抑制组成性和 IL-6 诱导的磷酸化 STAT3（STAT3(Y705))，并呈剂量依赖性降低 STAT3 调节蛋白 Bcl-xL、Mcl-1、Survivin 和 CyclinD1 的水平。淫羊藿素还抑制 Janus 激活激酶-2（JAK2）的激活，而对其他关键信号通路（包括 AKT 和 MAPK）的激活作用很小。组成型激活形式的 STAT3 的表达阻断了淫羊藿素诱导的细胞凋亡，而针对 STAT3 的 siRNA 增强了细胞凋亡。最后，淫羊藿素在体内显著抑制 RCC 肿瘤生长，降低 STAT3 激活，并抑制肿瘤中的 Bcl-xL 和 Cyclin E 以及 VEGF 表达，从而与肿瘤血管生成减少相关。总的来说，这些结果表明淫羊藿素强烈抑制 STAT3 激活，是治疗肾细胞癌的潜在有效治疗选择。
