Tian Binqiang, Zhao Yingmei, Liang Tao, Ye Xuxiao, Li Zuowei, Yan Dongliang, Fu Qiang, Li Yonghui
a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
b Department of Gynaecology and Obstetrics , Shanghai Pudong Hospital, Fudan University Pudong Medical Center , Shanghai , China.
J Drug Target. 2017 Aug;25(7):626-636. doi: 10.1080/1061186X.2017.1306535. Epub 2017 Mar 26.
We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.
我们之前报道过姜黄素在大鼠膀胱癌发生模型中可抑制尿路上皮肿瘤的发展。在本研究中，我们报道姜黄素通过抑制IGF2以及IGF2介导的PI3K/AKT/mTOR信号通路来抑制尿路上皮肿瘤的发展。姜黄素在转录水平抑制IGF2表达，并降低膀胱癌细胞以及N-甲基-N-亚硝基脲（MNU）诱导的尿路上皮肿瘤组织中IGF1R和IRS-1的磷酸化水平。在膀胱癌细胞中异位表达IGF2和IGF1R（而非IGF1）可恢复这一过程，表明IGF2是姜黄素的作用靶点。此外，引入组成型活性AKT1可消除姜黄素对细胞增殖、迁移的抑制作用，并恢复4E-BP1和S6K1的磷酸化水平，表明姜黄素通过抑制IGF2介导的AKT/mTOR信号通路发挥作用。总之，我们的结果表明抑制IGF2以及IGF2介导的PI3K/AKT/mTOR信号通路是姜黄素的作用机制之一。我们的研究结果提示了一种针对由IGF2异常激活引起的人类膀胱癌的新治疗策略，这对于姜黄素的转化应用具有重要意义。
