Regulation of Tumorigenesis by the Perk Kinase

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，代谢营养物质，如 随着肿瘤体积的扩大，葡萄糖、氧气和生长因子变得有限 组织的血管性。在正常细胞中，营养物质供应的限制会引发生长停滞和/或细胞凋亡 从而防止在这种条件下的细胞膨胀。这项提案的目标是确定 内质网应激反应/未折叠蛋白反应(UPR)在感觉限制中的作用 葡萄糖的可利用性，从而促进细胞适应。PERK，三个近端信号之一 UPR的转导通路在调节细胞命运的决定中起着核心作用。支持生存的函数 从开发小分子抑制剂的角度来看，PERK已经引起了它相当大的兴趣 它的催化活性和希望这种抑制剂将具有强大的抗肿瘤活性。事实上，在 在之前的资金周期中，我们证明了抑制PERK对转移性肿瘤具有潜在的临床益处 乳腺癌。然而，由于PERK还具有促凋亡和抗增殖活性，它还可以 表现出肿瘤抑制活性。核心是我们有能力有效地瞄准福利是完全理解的 其抗增殖/促凋亡以及促进生存的功能。在前期工作中，我们 提供证据表明，虽然PERK起促进黑色素瘤进展的作用，但它的功能与 一种有效的黑色素瘤启动抑制因子。在本提案中，我们描述了三个综合目标，重点是 PERK在黑色素瘤发生中的作用阐明(目标1)--抗PERK的潜在疗效 靶向治疗(AIM 2)和肿瘤源性PERK突变体的鉴定及其在肿瘤中的作用 启动/进展(目标3)。这些研究将为以下机制提供关键的新见解 PERK蛋白激酶调节细胞的动态平衡以应对压力。AIMS与项目的接口 1和2通过对信号通路的共同兴趣来感知和响应代谢限制和 通过对脂类代谢的反应和调节。根据本文提出的工作得出的发现将 为新型抗癌药物的设计提供了依据。

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.