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.

抽象的 多形性胶质母细胞瘤 (GBM) 对当前的标准护理治疗仍然难以治愈，并且 与最后几个月的预后黯淡和生活质量差有关。内质 网状（ER）应激，从而导致未折叠蛋白反应的组成性激活 （UPR）是 GBM 的一个常见特征，与攻击性和攻击性增加有关 治疗抵抗。 Sec61 易位子是跨越 ER 的蛋白质传导通道 膜，对于客户蛋白的共易位易位至关重要。 Sec61 亚基 GBM 中的 ER 应激和编码 γ 亚基的基因 (SEC61G) 也会上调 被认为是 GBM 原癌基因。我们现在提供证据表明 Sec61 直接受到牵连 GBM 癌症干细胞 (GSC) 中的 ER 应激/UPR 信号传导。总的来说，我们的结果表明 Sec61 的药理失活会导致 BiP mRNA 水平的降低并防止 pro- 生存 UPR 信号传导，特别是通过 UPR 传感器肌醇需求酶 1 (IRE1)。 我们的中心假设是 Sec61 易位子是 UPR 信号传导的重要调节因子 GBM 中的蛋白质稳态。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 信号传导中的作用。 2) 评估治疗潜力 原位 GSC 小鼠模型中的药理学靶向 Sec61。这种多维 该方法将揭示 GBM 和 GSC 中 Sec61 易位子的肿瘤支持特性 探索安全靶向 Sec61 以获得治疗优势同时避免毒性的可行性 由于分泌蛋白生物合成的非特异性抑制。这个早期临床前阶段 研究预计将为新设计的合成 Sec61 的未来发展提供信息 用于治疗 GBM 和其他侵袭性人类癌症的抑制剂，其特征是高 适应性 ER 应激水平。