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: 8855244
• 负责人: MOIRA SAUANE
• 金额: $ 28.91万
• 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/8855244
• 关键词: 5' Untranslated Regions; Adverse effects; Affinity; Antineoplastic Agents; Apoptosis; Binding; Biological Markers; Calcium; Cause of Death; Cell Proliferation; Cells; Cessation of life; Collaborations; Complex; Cyclin D1; Down-Regulation; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Experimental Models; Fura-2; Gene Cluster; Genes; Goals; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Housekeeping; Human; Immunoglobulins; Interleukin-24; Laboratories; Letters; Link; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Molecular Profiling; Normal Cell; Oncogenic; PERK kinase; Peptide Initiation Factors; Phosphorylation; Phosphotransferases; Physiological; Play; Point Mutation; Polyribosomes; Protein C; Proteins; Recycling; Research; Role; Signal Transduction; Solid Neoplasm; Stream; Structure; Therapeutic; Toxic effect; Translating; Translation Initiation; Translations; Tumor Suppression; 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; cellular engineering; endoplasmic reticulum stress; inhibitor/antagonist; killings; malignant phenotype; medical schools; meetings; 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（由申请人提供）：该项目的总体目标是扩大我们对将翻译起始抑制与白介素 24 (IL-24) 触发的细胞凋亡和肿瘤抑制联系起来的细胞和分子机制的理解。 24作为治疗实体瘤的基因疗法证明IL-24是有效且安全的，这一提议与当前的观点一致，即现代抗癌治疗必须具有靶向性，抑制癌症的生长。影响最小通过靶向负责癌症发生、维持和/或进展的基本机制，可以实现低毒性的有效抗癌剂。内质网 (ER) 应激的激活，进而诱导真核起始因子 2 α (eIF2α) 的磷酸化和 he 的可用性。正如最初认为的那样，三元复合物不仅控制总体翻译速率，而且还控制特定基因簇的表达。大多数致癌蛋白的严格翻译控制解释了不受限制的翻译起始与恶性转化之间的联系，这在两个实验中都已得到充分证实。在模型和许多人类癌症中，过度表达翻译起始因子的磷酸化 eIF2α 以高亲和力与鸟嘌呤核苷酸交换因子 eIF2B 结合，从而抑制 eIF2*GDP 的再循环。 eIF2*GTP，耗尽启动新一轮翻译所需的三元复合物 众所周知，部分耗尽 ER Ca++ 储备会激活 eIF2 激酶，从而磷酸化 eIF2 并由此限制翻译起始速率。证明 IL-24 诱导结合免疫球蛋白 (BiP) 和 C/-EBP 同源蛋白 (CHOP) 的表达，这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限制，并且该 IL-24： Sig1R 是 IL-24 诱导的 ER 应激、钙动员、eIF2α 磷酸化和癌细胞凋亡的关键上游信号。为了继续努力描述 IL-24 作为翻译起始抑制剂的癌细胞特异性作用，我们将 1) 使用 Cameleon 钙指示蛋白直接评估 IL-24 处理后 ER 储存的钙含量。 （具体目标 1）、2）确定三元复合物的消耗是否介导 IL-24 的抗癌作用，（具体目标 2）和 3）确定 Sig1R 对IL-24 介导的翻译起始抑制（具体目标 3）。 将与哈佛医学院的 Jose A. Halperin 博士合作，他是癌症治疗靶向翻译启动方面的专家。