Molecular Mechanisms Underlying Cell Survival During Endoplasmic Reticulum Stress

摘要 内质网应激是细胞应激的一种形式，我们的细胞 在正常的生理条件下，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变。在面临内质网压力时，细胞最初试图 通过激活被称为未折叠蛋白的保守信号通路来恢复正常功能 回应(普遍定期审议)。然而，如果压力变成慢性的，体内的动态平衡没有恢复 在一个合理的时间框架内，UPR最终会使细胞发生程序性死亡。显示单元格 做出这个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 细胞由于葡萄糖代谢率高和低氧条件而表现出内质网应激 导致内质网中糖基化不足、错误折叠的蛋白质堆积。癌症的能力 细胞成功地适应内质网应激并继续存活与它们的 侵袭性/恶性和化疗耐药性。因此，为了能够从分子上设计出有效的 有针对性的治疗策略，描述赋予癌细胞的机制是至关重要的 在面对内质网应激时具有细胞保护作用。这项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。 中心假设是促生存的Akt通路调节UPR，以确定 总体细胞命运，我们将(A)目标1：研究Akt在调节起源信号中的作用 来自UPR传感器对压力的响应(B)目标2：确定Akt的机制 在内质网应激过程中以非规范的方式激活。我们的结果可能会导致重要的 关于癌细胞如何在内质网应激中获得细胞保护优势的启示 延长生存时间。我们提案的成功完成将在以下方面推动该领域的发展 增强我们对令人着迷的细胞生物学过程的基础知识，以及发现 抑制癌细胞存活的新的关键靶点。

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.