Translocon-regulated ER proteostasis in glioblastoma

胶质母细胞瘤中易位蛋白调节的内质网蛋白稳态

• 批准号: 10301296
• 负责人: Christian Elias Badr
• 金额: $ 45.29万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301296
• 关键词: Acidosis; Biochemical; Brain; Cell Death; Cell Maintenance; Cell Survival; Chemicals; Chromosomes; Client; Complex; Cytoprotection; Dependence; Drug Kinetics; Endogenous Factors; Endoplasmic Reticulum; Ensure; Environment; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Feedback; Future; GRP78 gene; Gatekeeping; Genes; Genetic; Genetic Transcription; Genomic Instability; Glioblastoma; Glioma; Growth; Human; Hypoxia; Inositol; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Membrane; Messenger RNA; Molecular Chaperones; Mus; Natural Products; Nutrient; Oncogenic; Output; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Primary Brain Neoplasms; Prognosis; Proliferating; Property; Protein Biosynthesis; Protein Secretion; Proteins; Proto-Oncogenes; Quality of life; RNA Splicing; Recurrence; Refractory; Ribonucleases; Role; Safety; Signal Transduction; Stress; Survival Rate; Testing; Therapeutic; Time; Toxic effect; Tumor Stem Cells; XBP1 gene; Xenograft Model; Xenograft procedure; analog; cancer stem cell; design; endoplasmic reticulum stress; in vivo; inhibitor/antagonist; mRNA Decay; mRNA Expression; mouse model; neoplastic cell; overexpression; pre-clinical research; preservation; prevent; proteostasis; prototype; response; secretory protein; sensor; small molecule inhibitor; standard of care; stem cell model; stem cells; temozolomide; therapeutic target; therapy resistant; tumor; tumor growth; tumor initiation

Abstract Glioblastoma multiforme (GBM) remains refractory to current standard-of-care treatment and is associated with a bleak prognosis and poor quality of life in the final months. Endoplasmic reticulum (ER) stress, and consequently a constitutive activation of the unfolded protein response (UPR), is a common feature of GBM and has been linked to increased aggressiveness and therapeutic resistance. The Sec61 translocon is a protein-conducing channel which spans the ER membrane and is essential for cotranslocational translocation of client proteins. Sec61 subunits are also upregulated by ER stress in GBM and the gene encoding the gamma subunit (SEC61G) is considered a GBM proto-oncogene. We now present evidence that Sec61 is directly implicated in ER stress/UPR signaling in GBM cancer stem cells (GSCs). Overall, our results suggest that pharmacological inactivation of Sec61 results in depletion of BiP mRNA levels and prevents pro- survival UPR signaling particularly through the UPR sensor inositol-requiring enzyme 1 (IRE1). Our central hypothesis is that Sec61 translocon is an essential regulator of UPR signaling and proteostasis in GBM. We will test this hypothesis through the following specific aims: 1) Define the role of Sec61 in UPR signaling in GBM. 2) Evaluate the therapeutic potential of pharmacological targeting Sec61 in orthotopic GSCs mouse models. This multidimensional approach will reveal the tumor-supportive properties of Sec61 translocon in GBM and GSCs and explore the feasibility of safely targeting Sec61 for therapeutic advantage while avoiding toxicities due to non-specific inhibition of secretory protein biosynthesis. This early stage pre-clinical research is expected to inform the future advancement of newly designed synthetic Sec61 inhibitors for the treatment of GBM and other aggressive human cancers characterized by high levels of adaptive ER stress.

摘要 多形性胶质母细胞瘤(GBM)对目前的标准治疗方案仍然难以奏效 与最后几个月的黯淡预后和较差的生活质量有关。内质网 网状(ER)应激，从而导致未折叠蛋白反应的结构性激活 (普遍定期审议)，是GBM的一个共同特征，并已与更具侵略性和 治疗抵抗力。Sec61转运子是一种跨越内质网的蛋白质传导通道 膜，对客户蛋白的共转位是必不可少的。Sec61亚基 在GBM和编码伽马亚基的基因(SEC61G)中也受到内质网应激的上调 被认为是GBM原癌基因。我们现在提交证据表明Sec61直接牵涉其中 在GBM肿瘤干细胞(GSCs)的ER应激/UPR信号转导中。总体而言，我们的结果表明 Sec61的药理失活会导致Bip mRNA水平的耗竭，并阻止PRO。 存活UPR信号，特别是通过UPR传感器肌醇需要酶1(IRE1)。 我们的中心假设是Sec61转运子是UPR信号的重要调节因子，并且 基底膜中的蛋白平衡。我们将通过以下具体目标来检验这一假设：1)定义 Sec61在GBM中UPR信号转导中的作用2)评估治疗潜力 GSCs小鼠模型的药理学靶向Sec61。这是多维的 方法将揭示Sec61转位蛋白在GBM和GSCs中的肿瘤支持特性 探讨安全靶向Sec61在避免毒副作用的同时获得治疗优势的可行性 由于非特异性抑制分泌性蛋白质的生物合成。这一早期的临床前阶段 研究有望为新设计的合成Sec61的未来进展提供信息 用于治疗GBM和其他具有高侵袭性特征的人类癌症的抑制剂 适应性内质网应激水平。