Yu Siwang, Shen Guoxiang, Khor Tin Oo, Kim Jung-Hwan, Kong Ah-Ng Tony
Department of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Mol Cancer Ther. 2008 Sep;7(9):2609-20. doi: 10.1158/1535-7163.MCT-07-2400.
Akt/mammalian target of rapamycin (mTOR) signaling plays an important role in tumorigenesis and is dysregulated in many tumors, especially metastatic prostate cancers. Curcumin has been shown to effectively prevent or inhibit prostate cancer in vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains unclear. Here, we show that curcumin concentration- and time-dependently inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1. Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin-mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin-mediated inhibition of Akt/mTOR signaling. Curcumin also activated 5'-AMP-activated protein kinase and mitogen-activated protein kinases; however, inhibition of these kinases failed to rescue the inhibition by curcumin. Finally, it was shown that the inhibition of Akt/mTOR signaling by curcumin is resulted from calyculin A-sensitive protein phosphatase-dependent dephosphorylation. Our study reveals the profound effects of curcumin on the Akt/mTOR signaling network in PC-3 cells and provides new mechanisms for the anticancer effects of curcumin.
Akt/雷帕霉素哺乳动物靶蛋白（mTOR）信号传导在肿瘤发生过程中发挥重要作用，且在许多肿瘤尤其是转移性前列腺癌中失调。姜黄素已被证明可在体内有效预防或抑制前列腺癌，并在体外抑制Akt/mTOR信号传导，但其机制仍不清楚。在此，我们表明姜黄素在人前列腺癌PC-3细胞中呈浓度和时间依赖性地抑制Akt、mTOR及其下游底物的磷酸化，且这种抑制作用在磷脂酰肌醇3激酶和磷脂酰肌醇依赖性激酶1的下游起作用。组成型激活的Akt过表达或通过小干扰RNA或基因敲除破坏TSC1-TSC2复合物仅部分恢复了姜黄素介导的对mTOR和下游信号传导的抑制，表明它们不是姜黄素介导的抑制Akt/mTOR信号传导的主要效应器。姜黄素还激活了5'-AMP激活的蛋白激酶和丝裂原激活的蛋白激酶；然而，抑制这些激酶未能挽救姜黄素的抑制作用。最后，结果表明姜黄素对Akt/mTOR信号传导的抑制是由钙调磷酸酶敏感的蛋白磷酸酶依赖性去磷酸化引起的。我们的研究揭示了姜黄素对PC-3细胞中Akt/mTOR信号网络的深远影响，并为姜黄素的抗癌作用提供了新机制。
