Turning Inhibition of Translation Initiation into Cancer Therapy

将翻译起始抑制转化为癌症治疗

• 批准号: 9319703
• 负责人: MOIRA SAUANE
• 金额: $ 24.75万
• 依托单位: HERBERT H. LEHMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319703
• 关键词: 5' Untranslated Regions; Adverse effects; Affinity; Antineoplastic Agents; Apoptosis; Binding; Biological Markers; Calcium; Calcium Channel; Cause of Death; Cell Proliferation; Cells; Cessation of life; Collaborations; Complex; Cyclin D1; Down-Regulation; Endoplasmic Reticulum; Engineering; Eukaryotic Initiation Factor-2; Experimental Models; Fura-2; Gene Cluster; Genes; Goals; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Housekeeping; Human; Immunoglobulin binding proteins; Interleukin-24; Laboratories; Letters; Link; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Modernization; Molecular; Normal Cell; Oncogenic; PERK kinase; Peptide Initiation Factors; Phosphorylation; Phosphotransferases; Physiological; Play; Point Mutation; Polyribosomes; Proteins; Recycling; Research; Role; Signal Transduction; Solid Neoplasm; Structure; Therapeutic; Toxic effect; Translating; Translation Initiation; Translations; Tumor Suppression; Untranslated Regions; Up-Regulation; Woman; Work; activating transcription factor 4; age group; anti-cancer therapeutic; anticancer activity; base; calcium indicator; cancer cell; cancer therapy; cell growth; cell growth regulation; cell type; endoplasmic reticulum stress; inhibitor/antagonist; killings; malignant phenotype; medical schools; men; mutant; neoplastic cell; new therapeutic target; overexpression; public health relevance; release of sequestered calcium ion into cytoplasm; research clinical testing; restraint; sigma-1 receptor; transcription factor CHOP; tumor progression

 DESCRIPTION (provided by applicant): The overall goal of this project is to expand our understanding of the cellular and molecular mechanisms that link translation initiation inhibition to apoptosis and tumor suppression triggered by Interleukin-24 (IL-24). Clinical testing of IL-24 as a gene-based therapeutic for the treatment of solid tumors demonstrated that IL-24 is efficacious and is safe. This proposal is consistent with the current view that modern anti-cancer therapy must be target-specific, inhibit the growth of cancer with minimal effect on normal cells, and that effective anti- cancer agents of low toxicity can be achieved by targeting the fundamental mechanisms responsible for the genesis, maintenance, and/or progression of cancer. I have shown that IL-24 causes partial depletion of intracellular Ca++ and activation of endoplasmic reticulum (ER) stress, which in turn induces inhibitory phosphorylation of eukaryotic initiation factor 2 alpha (eIF2). Phosphorylation of eIF2 and the availability of he ternary complex control not only the overall rate of translation, as initially thought, but also th expression of specific gene clusters. The tight translational control of most oncogenic proteins explains the link between unrestricted translation initiation and malignant transformation that has been well established in both experimental models and in numerous human cancers that overexpress translation initiation factors. Phosphorylated eIF2 binds with high affinity to the guanine nucleotide exchange factor eIF2B and thereby inhibits recycling of eIF2*GDP into eIF2*GTP, depleting the ternary complex necessary to initiate a new round of translation. It is well established that partial depletion of ER Ca++ stores activates the eIF2 kinases that phosphorylate eIF2 and thereby limits the rate of translation initiation. Furthermore, I have demonstrated that IL-24 induces expression of Binding immunoglobulin protein (BiP) and C/-EBP homologous protein (CHOP), two down-stream markers of ternary complex abundance. The working hypothesis of this application is that IL-24 exerts anticancer activities because it helps restore physiological restraints on translation initiation. I have demonstrated that Sigma 1 Receptor (Sig1R) interacts with IL-24 and that this IL-24:Sig1R is a critical upstream signal for IL-24-induced ER-stress, calcium mobilization, phosphorylation of eIF2 and apoptosis on cancer cells. In this application we propose to continue our efforts to characterize the cancer cell- specific actions of IL-24 as an inhibitor of translation initiation. Specifically, we will 1)use cameleon calcium indicator proteins to assess directly the calcium content of the ER-stores after IL-24 treatment (Specific Aim 1), 2) determine whether depletion of the ternary complex mediates the anticancer effect of IL-24, (Specific Aim 2), and 3) determine the role of Sig1R on IL-24-mediated inhibition of translation initiation (Specific Aim 3). For these proposed studies we will collaborate with Dr. Jose A. Halperin, from Harvard Medical School, and expert on targeting translation initiation for cancer therapy.

 描述（由适用提供）：该项目的总体目标是扩展我们对将翻译起始抑制作用与凋亡和肿瘤抑制的细胞和分子机制的理解（IL-24）（IL-24）。 IL-24作为基于基因治疗的实体瘤治疗的临床测试表明IL-24是有效且安全的。该提案与当前的观点一致，即现代抗癌治疗必须是针对目标特异性的，抑制癌症的生长，对正常细胞的影响最小，并且可以通过靶向负责癌症的发生，维持和/或进展的有效低毒性抗癌药来实现。我已经表明，IL-24会导致细胞内Ca ++的部分消耗和内质网应激的激活，这又诱导了真核起始因子2α（EIF2）的抑制性磷酸化。 EIF2的磷酸化和HE三元复合物控制的可用性不仅是最初认为的整体翻译速率，而且还表达了特定基因簇的TH表达。大多数致癌蛋白的紧密翻译控制解释了无限制的翻译计划与恶性转化之间的联系，这些联系在实验模型中已经很好地确定，在许多过表达翻译倡议因素的人类癌症中。磷酸化的EIF2与Guanine核交换因子EIF2B具有高亲和力结合，从而抑制将EIF2*GDP回收到EIF2*GTP中，从而耗尽了启动新轮流所需的三元复合物。众所周知，ER CA ++存储的部分耗竭激活了磷酸化EIF2的EIF2激酶，从而限制了翻译速度。此外，我已经证明了IL-24影响结合免疫球蛋白蛋白（BIP）和C/-EBP同源蛋白（CHOP）的表达，这是三元复合物抽象的两个下游标记。该应用的工作假设是IL-24发挥抗癌活性，因为它有助于恢复翻译起始的生理约束。我已经证明了Sigma 1受体（SIG1R）与IL-24相互作用，并且该IL-24：SIG1R是IL-24诱导的ER压力，钙动员，EIF2的磷酸化和癌细胞凋亡的关键上游信号。在此应用中，我们建议继续我们的努力来表征IL-24作为翻译计划的抑制剂的癌细胞特异性作用。具体，我们将1）使用Cameleon钙指示剂蛋白直接评估IL-24处理后ER商店的钙含量（特定目的1），2）确定三元复合物的消耗是否介导IL-24（特定目标2）和3）确定SIG1R对IL-24介导的IL-24介导的作用的作用（特异性目标2）（特定目标2）（特定目标2）的抗抗菌作用。对于这些提出的研究，我们 将与哈佛医学院的Jose A. Halperin博士合作，以及针对癌症治疗翻译启动的专家。