Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio, USA.
PLoS One. 2013 May 1;8(5):e61896. doi: 10.1371/journal.pone.0061896. Print 2013.
Survivin is a unique member of the inhibitor of apoptosis (IAP) proteins that is overexpressed in numerous cancers through poorly defined mechanisms. One such mechanism may be through constitutive activation of the insulin-like growth factor-I (IGF-I) signaling pathway, implicated in the development and progression of prostate cancer. Using the pre-neoplastic NRP-152 rat prostate cell line as a model, we showed that IGF-I induces Survivin expression, and that silencing Survivin by lentiviral-mediated small hairpin RNA (shRNA) represses IGF-I-stimulated cell growth, implicating Survivin as a mediator of this growth response. Moreover, our data support that the induction of Survivin by IGF-I occurs through a transcriptional mechanism that is mediated in part by the PI3K/Akt/mTORC1 pathway. Use of various Survivin promoter-luciferase constructs revealed that the CDE and CHR response elements in the proximal region of the Survivin promoter are involved in this IGF-I response. Transforming growth factor (TGF-β) signaling antagonists similarly activated the Surivin promoter and rendered cells refractory to further promoter activation by IGF-I. IGF-I suppressed levels of phospho-Smads 2 and 3 with kinetics similar to that of Survivin induction. Suppression of TGF-β signaling, either by TGF-β receptor kinase inhibitors or by silencing Smads 2 and 3, induced Survivin expression and promoted cell growth similar to that induced by IGF-I. TGF-β receptor antagonists also rescued cells from down-regulation of Survivin expression and growth suppression by pharmacological inhibitors of PI3K, Akt, MEK and mTOR. Sh-RNA gene silencing studies suggest that mTORC1 induces while mTORC2 represses the expression of Survivin by IGF-I. Taken together, these results suggest that IGF-I signaling through a PI3K/Akt/mTORC1 mechanism elevates expression of Survivin and promotes growth of prostate epithelial cells by suppressing Smad-dependent autocrine TGF-β signaling.
生存素是凋亡抑制因子（IAP）蛋白家族中的一个独特成员，其在许多癌症中通过尚未明确的机制过度表达。其中一种机制可能是通过胰岛素样生长因子-I（IGF-I）信号通路的组成性激活，该通路与前列腺癌的发生和发展有关。我们使用前癌变的 NRP-152 大鼠前列腺细胞系作为模型，表明 IGF-I 诱导生存素表达，并且通过慢病毒介导的短发夹 RNA（shRNA）沉默生存素抑制 IGF-I 刺激的细胞生长，表明生存素是这种生长反应的介质。此外，我们的数据支持 IGF-I 诱导生存素的发生是通过转录机制介导的，部分是由 PI3K/Akt/mTORC1 途径介导的。使用各种生存素启动子荧光素酶构建体表明，生存素启动子近端区域的 CDE 和 CHR 反应元件参与了这种 IGF-I 反应。转化生长因子（TGF-β）信号拮抗剂同样激活了 Surivin 启动子，并使细胞对 IGF-I 的进一步启动子激活产生抗性。IGF-I 以类似于生存素诱导的动力学抑制磷酸化 Smads 2 和 3 的水平。TGF-β 信号的抑制，无论是通过 TGF-β 受体激酶抑制剂还是通过沉默 Smads 2 和 3，都诱导生存素表达并促进细胞生长，类似于 IGF-I 诱导的生长。TGF-β 受体拮抗剂还通过药理抑制剂 PI3K、Akt、MEK 和 mTOR 挽救细胞免于生存素表达的下调和生长抑制。Sh-RNA 基因沉默研究表明，mTORC1 通过 PI3K/Akt/mTORC1 机制诱导 IGF-I 诱导的生存素表达，而 mTORC2 抑制生存素的表达。总之，这些结果表明，IGF-I 信号通过 PI3K/Akt/mTORC1 机制上调生存素表达，并通过抑制依赖 Smad 的自分泌 TGF-β 信号来促进前列腺上皮细胞的生长。
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