Molecular Mechanisms Underlying Cell Survival During Endoplasmic Reticulum Stress

摘要 内质网（ER）应激是一种细胞应激的形式，我们的细胞都经历过 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、糖尿病和神经变性。面对内质网应激，细胞最初试图 通过激活一种称为未折叠蛋白的保守信号通路来恢复正常功能 答复（普遍定期审议）。然而，如果压力变成慢性的，体内平衡没有恢复， 在一个合理的时间框架内，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却鲜为人知的现象。癌 细胞由于它们的高葡萄糖代谢率和缺氧条件而表现出ER应激 导致糖基化不足、错误折叠的蛋白质在ER中积累。癌症的能力 细胞成功地适应ER应激并继续存活与其 侵袭性/恶性和化学抗性。因此，为了能够设计有效的分子 因此，为了制定有针对性的治疗策略，至关重要的是阐明赋予癌细胞 在面对内质网应激时具有细胞保护作用。本提案的主要目的是调查 通过内质网应激促进细胞存活的分子机制。 核心假设是促生存Akt通路调节UPR以确定细胞的存活率。 （A）目的1：研究Akt在调节细胞信号来源中的作用， 目的2：确定Akt从UPR传感器响应应力的机制（B） 在ER应激期间以非典型方式激活。我们的研究结果可能会导致重要的 揭示了癌细胞如何在内质网应激期间获得细胞保护优势， 延长生存期。我们的提案的成功完成将在以下方面推动该领域的发展： 增强了我们对一个迷人的细胞生物学过程的基础知识， 抑制癌细胞存活的新的关键目标。

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.