Development of an Anti-Cancer Approach Through a Novel Pathway of Translational Regulation

摘要 STAT3（Signal Transducer and Activator of Transcription 3）是一种转录调节因子，在转录过程中起着重要的作用 在细胞的恶性转化、肿瘤生长和转移中。STAT3活性或表达是 在70%的人类肿瘤中上调，导致癌症快速进展，因此它是一种潜在的 癌症治疗中的药理学靶点。已经证明，STAT3敲低减少了异常的细胞凋亡。 细胞生长然而，STAT3活性的直接和间接抑制剂没有提供预期的功效， 需要寻找STAT3抑制的替代策略。STAT3异常表达的存在 在不同类型的肿瘤中的作用以及通过降低STAT3表达治疗癌症的潜在能力 决定了研究的重要意义。本项目的中心思想是基于STAT3的控制 通过调节新途径的组分在核糖体上合成期间表达 我们最近发现的。RAPP（Regulation of Aberrant Protein Production）途径 调节蛋白质合成，降解蛋白质的mRNA，这些蛋白质在其合成过程中不能正确相互作用。 在核糖体上合成。我们的假设是RAPP翻译调节因子可能被用于 控制STAT3表达，从而限制细胞增殖和肿瘤生长。这个概念 以前从未探索过STAT3的调节类型，对STAT3的翻译伴侣知之甚少， 关于它们的调节以控制STAT3表达，从而证明了该项目的新奇。我们的初步 数据表明RAPP途径参与STAT3的调节。具体目标如下： 为该项目设计的：（1）在其在核糖体上合成期间鉴定新的STAT3翻译配偶体， 和（2）检验RAPP翻译调节因子可被调节以降低STAT3的假设 表达和癌细胞增殖。该研究基于独特的检测技术， 通过位点特异性光交联和iPINCH方法鉴定翻译过程中的蛋白质。我们将 使用候选和无偏的方法来测试STAT3控制中的RAPP调节器。实验还将 涉及细胞培养模型和RNA干扰技术或过度生产，以验证参与的 STAT3调节中的RAPP组件。在这个项目中，我们将确定潜在的抗癌特性的 通过测量癌细胞增殖和凋亡调节RAPP。该提案的成功将有助于 为未来的动物模型研究和化学调节剂（潜在药物）的使用奠定了基础， 开发新的抗癌药物。这一建议可能会导致开发概念上新的 癌症药物治疗的方向。

ABSTRACT STAT3 (Signal Transducer and Activator of Transcription 3) is a transcriptional regulator that plays crucial role in malignant transformation of the cells, tumor growth and metastasis. STAT3 activity or expression is upregulated in 70% of human tumors contributing to a rapid cancer progression and therefore it is a potential pharmacological target in cancer treatments. It was demonstrated that STAT3 knockdown reduced abnormal cell growth. However, direct and indirect inhibitors of STAT3 activity did not provide expected efficacy, demanding search for alternative strategies for STAT3 inhibition. The presence of STAT3 aberrant expression in different types of tumors and potential ability to treat cancer through decrease of STAT3 expression determines high significance of the study. The central idea of the current project is based on control of STAT3 expression during its synthesis on the ribosome through modulation of components of the novel pathway recently discovered by us. The RAPP (Regulation of Aberrant Protein Production) pathway specifically regulates protein synthesis, degrading mRNAs of the proteins that do not properly interact during their synthesis on the ribosome. Our hypothesis is that the RAPP translational regulators may be used to control STAT3 expression and therefore restrict cell proliferation and tumor growth. The concept of this type of STAT3 regulation was never explored before, little is known about STAT3 translational partners and about their modulation to control STAT3 expression, thus demonstrating novelty of the project. Our preliminary data demonstrate that the RAPP pathway is involved in regulation of STAT3. The following specific aims are designed for this project: (1) identify novel STAT3 translational partners during its synthesis on the ribosome, and (2) test the hypothesis that RAPP translational regulators can be modulated to decrease STAT3 expression and cancer cell proliferation. The study is based on unique technologies for detection and identification of proteins during translation by site-specific photo-crosslinking and iPINCH approaches. We will use candidate and unbiased approaches to test RAPP regulators in STAT3 control. The experiments will also involve cell culture models and RNA interference techniques or overproduction to verify involvement of the RAPP components in STAT3 regulation. In this project we will determine potential anti-cancer properties of the RAPP modulation by measuring cancer cell proliferation and apoptosis. The success of the proposal will build a foundation for the future studies with animal models and use of chemical regulators (potential drugs) to develop new anti-cancer medicine. Potentially, this proposal will lead to development of conceptually new directions in pharmacological treatments of cancer.