Regulation of Tumorigenesis by the Perk Kinase

快速增殖的癌细胞必须在微环境中茁壮成长，其中代谢营养物， 当肿瘤体积扩大超过既定的体积时，葡萄糖、氧气和生长因子变得有限。 组织的血管分布。在正常细胞中，营养可用性的限制触发生长停滞和/或凋亡 从而防止细胞在这种条件下扩张。本提案的目的是确定 内质网应激反应/未折叠蛋白反应（UPR）在感知限制中的作用 从而促进细胞适应。PERK，三个近端信号之一 UPR的转导子在介导细胞命运决定中起核心作用。的促生存功能 PERK已经从开发小分子抗肿瘤抑制剂的角度获得了相当大的兴趣。 它的催化活性，并希望这种抑制剂将具有有效的抗肿瘤活性。的确， 在上一个资助周期中，我们证明了PERK抑制在转移性肿瘤中具有潜在的临床益处， 乳腺癌然而，由于PERK也具有促凋亡和抗增殖活性，因此它也可以 显示肿瘤抑制活性。我们有效定位PERK的核心能力是完全理解 它的抗增殖/促凋亡以及促生存功能。在前期工作中，我们 提供的证据表明，虽然PERK的功能，以促进黑色素瘤的进展，它矛盾的功能， 黑色素瘤启动的有效抑制剂。在本提案中，我们描述了三个综合目标， 在阐明PERK在黑色素瘤发生中的功能（目的1），抗PERK的潜在疗效 靶向治疗（目标2）和肿瘤来源的PERK突变体的鉴定及其在肿瘤中的作用 启动/进展（目标3）。这些研究将提供关键的新的洞察机制， PERK蛋白激酶响应于应激调节细胞内稳态。目标与项目的接口 1和2通过共同的利益，在信号转导途径的感觉和响应代谢限制， 通过对脂质代谢的反应和调节。本文提出的工作所产生的结果将 为设计新型抗癌治疗药物提供了基础。

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. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis thereby preventing cellular expansion under such conditions. The goal of this proposal is to determine the role of the endoplasmic reticulum stress response/Unfolded Protein Response (UPR) in sensing limitations in glucose availability and thereby facilitating cellular adaptation. PERK, one of three proximal signal transducers of the UPR plays a central role in mediating cell fate decisions. The pro-survival function of PERK has garnered it considerable interest from the point of view of developing small molecule inhibitors of its catalytic activity and the hope that such inhibitors would have potent anti-tumor activity. Indeed, in the previous funding cycle, we demonstrated that PERK inhibition is of potential clinical benefit in metastatic breast cancer. However, because PERK also pro-apoptotic and anti-proliferative activities, it could also exhibit tumor suppressive activity. Central our ability to effectively target PERK is a complete understanding of both its anti-proliferative/pro-apoptotic as well as pro-survival functions. In our preliminary work, we provide evidence that while PERK functions to facilitate melanoma progression, it paradoxically functions as a potent suppressor of melanoma initiation. In this proposal, we describe three integrated aims that focus on the elucidation of PERK function in melanoma initiation (Aim 1), the potential efficacy of anti-PERK targeted therapy (Aim 2) and the identification of tumor-derived PERK mutants and their role in tumor initiation/progression (Aim 3). These studies will provide critical new insight into the mechanisms whereby the PERK protein kinase regulates cell homeostasis in response to stress. The aims interface with Projects 1 and 2 through common interests in signaling pathways that sense and respond to metabolic limitation and through response and regulation of lipid metabolism. The findings steming from work proposed herein will provide a foundation for the design of novel anti-cancer therpeutics.