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）对目前的标准治疗仍然是难治性的， 与最后几个月的预后和生活质量差有关。内质 内质网（ER）应激，并因此未折叠蛋白反应的组成性激活 (UPR)是GBM的一个共同特征，与攻击性增加有关， 治疗抵抗Sec 61转位子是一种跨内质网的蛋白质传导通道 膜和客户蛋白的共易位是必不可少的。Sec 61亚基 也被GBM中的ER应激和编码γ亚基的基因（SEC 61 G）上调 被认为是GBM原癌基因。我们现在提出证据表明Sec 61与 在GBM癌症干细胞（GSC）中的ER应激/UPR信号传导中。总的来说，我们的研究结果表明， Sec 61的药理学失活导致BiP mRNA水平的耗竭，并阻止了前 存活UPR信号传导，特别是通过UPR传感器肌醇需要酶1（IRE 1）。 我们的中心假设是Sec 61转座子是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 Sec 61在GBM中UPR信号传导中的作用。2)评估以下治疗潜力： 在原位GSC小鼠模型中药理学靶向Sec 61。这一多层面 这种方法将揭示GBM和GSC中Sec 61易位子的肿瘤支持特性， 探索安全靶向Sec 61的可行性，以获得治疗优势，同时避免毒性 这是由于分泌蛋白生物合成的非特异性抑制。这种早期临床前 这项研究有望为新设计的合成Sec 61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， 适应性ER应激水平。