Pdcd4-Rictor Interaction in Suppression of Lung Tumorigenesis

项目摘要/摘要 肺癌是美国癌症相关死亡的主要原因。高死亡率并不是 不仅由于缺乏有效的早期检测，而且由于目前可用的肿瘤反应较差 治疗。这些都强调了更好地了解肺的生物学事件和机制的迫切需要 抑制癌症，以及需要专门针对这些疾病的重要的新治疗方法 提高存活率的过程。肺癌主要分为两类：小细胞肺癌(SCLC) 和非小细胞肺癌(NSCLC)，后者占所有病例的80%-85%。一个新的子集 最近在小细胞肺癌和非小细胞肺癌中发现了雷帕霉素不敏感的伴发肺癌 扩增出mTOR(Rictor)基因。Rictor是哺乳动物雷帕霉素靶标的重要组成部分 复合体2(MTORC2)，是mTORC2复合体活性和完整性所必需的。激活mTORC2结果 在促进癌细胞增殖和存活方面。这个应用程序建立在令人兴奋的初步数据基础上 程序性细胞死亡4(Pdcd4)通过Rictor结合域(RBD)与Rictor结合以抑制mTORC2 活性、6-phosphofructo-2-kinase/fructose-2，6-biphosphatase-3水平、细胞增殖和集落 队形。此外，含有RBD的多肽可以特异性地抑制mTORC2，但不能抑制mTORC1。我们的数据 进一步证明RBD多肽对培养细胞和裸鼠的NSCLC增殖有抑制作用。这个 中心假说是Pdcd4-Rictor结合特异性地抑制mTORC2优先抑制 通过诱导蛋白酶体降解PFKFB3促进Rictor升高的非小细胞肺癌的增殖。为了测试这一点 假设，提出了三个具体目标：i)描述Pdcd4-Rictor结合干扰的机制 利用mTORC2活性抑制非小细胞肺癌的肿瘤生长；II)剖析Pdcd4-Rictor-mTORC2轴如何影响 PFKFB3的稳定性和代谢途径；iii)证明RBD多肽对mTORC2的特异性抑制 优先抑制Rictor升高的非小细胞肺癌的生长，以提高生存率。完成…… 拟议中的研究不仅将揭示mTORC2活性和PFKFB3的新调控机制 Pdcd4的表达，但也揭示了RBD多肽对非小细胞肺癌mTORC2特异性抑制的重要性 肿瘤发生学。预期的发现将指导我们制定与以下方面特别相关的新战略 Rictor升高的非小细胞肺癌患者的精确医学治疗。

Project Summary/Abstract Lung cancer is the leading cause of cancer-related deaths in the United States. The high mortality rate is not only due to the lack of effective early detection but also due to poor tumor response to currently available therapies. These underscore the urgent need to better understand the biological events and mechanism of lung cancer suppression, as is the need for important new therapeutic approaches that specifically target these processes to improve survival rates. Lung cancer is mainly divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the latter of which accounts for 80-85% of all cases. A new subset of lung cancer in both SCLC and NSCLC was recently identified in which Rapamycin-insensitive companion of mTOR (Rictor) gene is amplified. Rictor is an essential component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for mTORC2 complex activity and integrity. Activation of mTORC2 results in promotion of cancer cell proliferation and survival. This application builds on exciting preliminary data that Programmed cell death 4 (Pdcd4) bound with Rictor through a Rictor binding domain (RBD) to inhibit mTORC2 activity, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) level, cell proliferation, and colony formation. In addition, a peptide containing the RBD specifically inhibits mTORC2 but not mTORC1. Our data further demonstrated that the RBD peptide suppressed NSCLC proliferation in cultured cells and nude mice. The central hypothesis is that Pdcd4-Rictor binding specifically inhibits mTORC2 to preferentially suppress proliferation in Rictor-elevated NSCLC via induction of proteasomal degradation of PFKFB3. To test this hypothesis, three specific aims are proposed: i) Delineate the mechanism of how Pdcd4-Rictor binding interferes with mTORC2 activity to suppress tumor growth in NSCLC; ii) Dissect how Pdcd4-Rictor-mTORC2 axis impacts PFKFB3 stability and metabolic pathways; iii) Demonstrate that mTORC2-specific inhibition by RBD peptide preferentially suppresses the growth of Rictor-elevated NSCLC to improve survival rate. The accomplishment of the proposed study will not only uncover novel regulatory mechanisms of mTORC2 activity and PFKFB3 expression by Pdcd4 but also reveal the importance of mTORC2-specific inhibition by RBD peptide on NSCLC tumorigenesis. The expected findings will guide us to develop new strategies that are particularly relevant to precision medicine approaches for NSCLC patients with elevated Rictor.