Molecular Mechanisms Underlying Cell Survival During Endoplasmic Reticulum Stress

内质网应激期间细胞生存的分子机制

• 批准号: 10594944
• 负责人: Deepali Bhandari
• 金额: $ 11.06万
• 依托单位: CALIFORNIA STATE UNIVERSITY LONG BEACH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594944
• 关键词: Antineoplastic Agents; Apoptosis; Biochemical; Biological Assay; Biological Process; Cancer Prognosis; Cell Death; Cell Death Induction; Cell Survival; Cell physiology; Cells; Cellular Stress; Cellular biology; Centrifugation; Cessation of life; Chemoresistance; Chronic; Clinical Trials; Cytoprotection; Data; Degradation Pathway; Diabetes Mellitus; Disease; Endoplasmic Reticulum; Endowment; Exhibits; Functional disorder; Germ Cells; Goals; Homeostasis; Hypoxia; Immunofluorescence Microscopy; In Situ; Knowledge; Life; Ligation; Location; Luciferases; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Molecular Chaperones; Nerve Degeneration; Outcome; Pathologic; Pathway interactions; Phase; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Production; Proteins; Proteomics; Publishing; Regulation; Reporter; Research; Role; Secretory Cell; Signal Pathway; Signal Transduction; Site; Source; Stress; Techniques; Testing; Therapeutic Intervention; Time; Translations; Vesicle; Western Blotting; Work; World Health Organization; acquired drug resistance; cancer cell; cancer therapy; coping; design; endoplasmic reticulum stress; experience; fascinate; glucose metabolism; improved; insight; mimetics; misfolded protein; molecular targeted therapies; mortality; mutant; new therapeutic target; novel; programs; protein folding; protein protein interaction; recruit; response; sensor; small molecule; timeline; virtual

ABSTRACT Endoplasmic reticulum (ER) stress is a form of cellular stress that is experienced by our cells both under normal physiological conditions such as in professional secretory cells and disease states such as cancer, diabetes and neurodegeneration. Upon facing ER stress, cells initially attempt to restore normal function by activating a conserved signaling pathway called the unfolded protein response (UPR). However, if the stress becomes chronic and homeostasis is not restored within a reasonable timeframe, the UPR ultimately commits cells to programmed cell death. How cells make this life-or-death decision remains an exciting yet poorly understood phenomenon. Cancer cells exhibit ER stress due to their high rates of glucose metabolism and hypoxic conditions resulting in accumulation of underglycosylated, misfolded proteins in the ER. The ability of cancer cells to successfully adapt to ER stress and continue to survive has been correlated to their invasiveness/malignancy and chemoresistance. Thus, to be able to design effective molecularly targeted therapeutic strategies, it is crucial to delineate the mechanisms that endow cancer cells with cytoprotection in the face of ER stress. The main objective of this proposal is to investigate the molecular mechanisms that play a decisive role in promoting cell survival through ER stress. With the central hypothesis that the pro-survival Akt pathway regulates the UPR to determine the overall cell fate, we will (A) Aim 1: investigate the role of Akt in regulation of signals originating from the UPR sensors in response to stress (B) Aim 2: determine the mechanism by which Akt is activated in a non-canonical manner during ER stress. Our results will potentially lead to important revelations as to how cancer cells gain a cytoprotective advantage during ER stress resulting in prolonged survival. The successful completion of our proposal will advance the field in terms of enhancing our fundamental knowledge of a fascinating cell biological process as well as finding new and key targets for curbing cancer cell survival.

抽象的 内质网 (ER) 应激是细胞应激的一种形式，我们的细胞都会经历 在正常生理条件下，例如在专业分泌细胞和疾病状态下 例如癌症、糖尿病和神经退行性疾病。面对内质网应激时，细胞最初会尝试 通过激活称为未折叠蛋白的保守信号通路恢复正常功能 回应（普遍定期审议）。然而，如果压力变成慢性并且体内平衡没有在短时间内恢复 在合理的时间范围内，UPR 最终使细胞进入程序性细胞死亡。细胞如何 做出这种生死攸关的决定仍然是一个令人兴奋但人们知之甚少的现象。癌症 细胞由于葡萄糖代谢率高和缺氧条件而表现出内质网应激 导致内质网中糖基化不足、错误折叠的蛋白质积累。癌症的能力 细胞成功适应内质网应激并继续生存与其 侵袭性/恶性肿瘤和化疗耐药性。因此，能够设计有效的分子 靶向治疗策略，描绘赋予癌细胞的机制至关重要 面对 ER 应激时具有细胞保护作用。该提案的主要目的是调查 通过内质网应激促进细胞存活起决定性作用的分子机制。 中心假设是促生存 Akt 通路调节 UPR 来决定 总体细胞命运，我们将 (A) 目标 1：研究 Akt 在信号起源调节中的作用 来自 UPR 传感器对应力的响应 (B) 目标 2：确定 Akt 的机制 在内质网应激期间以非规范方式激活。我们的结果可能会带来重要的结果 关于癌细胞如何在内质网应激期间获得细胞保护优势的启示 延长生存期。我们提案的成功完成将推动该领域的发展 增强我们对令人着迷的细胞生物过程的基础知识以及发现 抑制癌细胞存活的新的关键目标。