The Unfolded Protein Response in Cancer

描述(由申请人提供)：本计划的总体目标是研究未折叠蛋白反应(UPR)信号通路在肿瘤稳态和肿瘤进展中的作用。快速增殖的癌细胞必须在这样的微环境中茁壮成长，在这种微环境中，随着肿瘤体积扩大到组织已建立的血管之外，葡萄糖、氧气和生长因子等代谢营养物质变得有限。UPR的功能是作为关键细胞营养物质的可获得性的传感器，例如对肿瘤生长和进展至关重要的葡萄糖和氧气。UPR，特别是PERK激酶，最近被证明促进了癌基因介导的肿瘤进展，这表明UPR也可能响应由异常的癌基因依赖信号触发的生物能量挑战。该计划项目正在询问的总体假设是，UPR，更具体地说，PERK激酶，作为肿瘤细胞自主和非自主生物能量应激的传感器发挥作用；随后PERK催化功能的激活促进肿瘤细胞对这种应激的适应，从而促进肿瘤进展。为了验证这一假设，已经开发了三个协同项目。项目1将评估微小RNA平衡依赖PERK的促生存和促凋亡功能的机制。关键的初步数据表明，miR-211是促凋亡因子CHOP的一种新的调节因子，并具有暂时调节CHOP表达的功能。项目2将询问PERK作为依赖c-Myc的生物能量和蛋白毒性应激的第一反应调节器的功能。通过调节蛋白质翻译的能力，PERK调节细胞对c-Myc的反应，从而确保生物能量能力与致癌需求相匹配，从而导致肿瘤生长而不是凋亡。项目3将测试一种假设，即肿瘤细胞激活UPR，也许更广泛地说，由于癌基因激活或氧气和/或营养缺乏而引起的综合应激反应(ISR)，从而获得逃避抗肿瘤药物的能力 1型干扰素的增殖和促凋亡作用，干扰素α/？通过这个项目的协同作用，我们将确定PERK如何平衡生长和凋亡(项目1和2)，PERK如何应对环境挑战(项目1和3)，以及肿瘤细胞如何利用PERK和UPR来适应癌基因触发的生物能量压力(项目1-2-3)。所有三个项目都将广泛使用科学核心B(细胞/组织形态核心)，并已建立起高度合作的工作关系。我们推测，本文提出的研究结果将为设计针对这一途径的新型抗癌治疗策略提供基础。

DESCRIPTION (provided by applicant): The overall goal of this Program is to investigate the role of the Unfolded Protein Response (UPR) signaling pathway in tumor homeostasis and tumor progression. Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. The UPR functions as a sensor of the availability of key cellular nutrients, such as glucose and oxygen that are criticall important for tumor growth and progression. The UPR and specifically the PERK kinase, has recently been shown to facilitate oncogene-mediated tumor progression, suggesting that the UPR may also respond to bioenergetic challenges triggered by aberrant oncogene-dependent signaling. The overall hypothesis being interrogated by this Program Project is that the UPR and more specifically, the PERK kinase, functions as a sensor of tumor ceil autonomous and non-autonomous bioenergetic stress; the ensuing activation of PERK catalytic function promotes tumor cell adaptation to this stress and thereby facilitates tumor progression. To test this hypothesis, three synergistic projects have been developed. Project 1 will evaluate mechanisms whereby a micro-RNA balances PERK-dependent pro-survival and pro-apoptotic functions. Key preliminary data suggest that miR-211 is a novel regulator of the pro-apoptotic factor, CHOP, and functions to temporally regulate CHOP expression. Project 2 will interrogate the function of PERK as a first response regulator of c- Myc-dependent bioenergetic and proteotoxic stress. Through its capacity to temper protein translation, PERK moderates cellular response to c-Myc thereby ensuring that bioenergetic capacity matches oncogenic demand resulting in tumor growth rather than apoptosis. Project 3 will test the hypothesis that tumor cells activate the UPR, and, perhaps, more broadly the Integrated Stress Response (ISR) due to oncogene activation or oxygen and/or nutritional deficit, and thereby acquire the ability to escape the anti proliferative and pro-apoptotic effects of Type 1 interferons, IFNα/ß. Through the synergistic functions of this Program, we will ascertain how PERK balances growth with apoptosis (Projects 1 and 2), how PERK responds to environmental challenge (Projects 1 and 3) and how tumor cells utilize PERK and the UPR to adapt to oncogene-triggered bioenergetic stress (Projects 1-2-3). All three projects will make extensive use of scientific Core B (Cell/Tissue Morphology Core) and have already established a working, highly collaborative relationship. It is our supposition that findings stemming from work proposed herein will provide a foundation for the design of novel anti-cancer treatment strategies targeting this pathway.