Phospholipase D-mTOR Survival Signals in Tumorigenesis

肿瘤发生中的磷脂酶 D-mTOR 存活信号

• 批准号: 8396559
• 负责人: DAVID A FOSTER
• 金额: $ 8.57万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-25 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396559
• 关键词: 1-Phosphatidylinositol 3-Kinase; Apoptosis; Apoptotic; Area; Breast; Cancer cell line; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Death; Cells; Colon; Ensure; Fostering; G1 Phase; Health; Human; In Vitro; Individual; Kidney; Lead; Lipids; Malignant Neoplasms; Mediating; Molecular; Molecular Medicine; Morphology; Mutation; Nutritional; Organism; Pathway interactions; Phosphatidic Acid; Phospholipase D; Play; Positioning Attribute; Process; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Sirolimus; Stomach; Stress; Therapeutic; Tissue Survival; Translational Research; cancer cell; cell growth; expectation; in vivo; innovation; mTOR protein; molecular pathology; novel; prevent; programs; response; second messenger; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Default apoptotic programs have been adapted as a first line of defense against cancer, and virtually all cancer cells have mutations that activate "survival signals" in order to suppress apoptosis. A central node in survival signaling is mTOR (the mammalian target of rapamycin). mTOR is activated in response to signals mediated by the phosphatidylinositol-3-kinase (PI3K) signaling pathway. However, more recently it has become apparent that mTOR is also targeted by signals that activate phospholipase D (PLD). PLD generates phosphatidic acid (PA), a lipid second messenger that interacts directly with mTOR in a manner that is competitive with rapamycin - and PA is required for the activation of mTOR. Importantly, PLD activity is elevated in several types of human cancer. PLD activity is elevated in many human cancer cells and is required for mTOR-mediated signals that are critical for survival and promote cell cycle progression. The CENTRAL HYPOTHESIS of the proposal is - Elevated PLD activity in human cancer cells promotes passage through a late G1 "Cell Growth Checkpoint" and suppresses default apoptotic programs. We are proposing that virtually all cancer cells must activate signals that allow passage through this checkpoint. SPECIFICALLY, we propose: 1) To determine how PLD-mTOR signaling impacts on cell cycle progression through a proposed Cell Growth Checkpoint; 2) To determine the mechanism by which PLD-generated PA regulates mTORC1 and mTORC2 in concert with other signaling inputs; and 3) To characterize signals that lead to elevated PLD activity in human cancer cell lines and to evaluate targeting these signals pharmacologically both in vitro and in vivo. We are proposing that a PLD-mTOR signaling pathway in human cancer cells represents a widely employed strategy by cancer cells to promote cell cycle progression and suppress default apoptotic programs. The studies proposed here will provide a framework for the rational targeting of an apparent large number of cancers that depend upon elevated PLD activity for G1 cell cycle progression and suppression of apoptosis. PUBLIC HEALTH RELEVANCE: The proposed study will evaluate the intracellular mechanisms that regulate phospholipase D (PLD) and mTOR in human cancer cells and the impact of these signals on a proposed "Cell Growth Checkpoint" in the G1 phase of the cell cycle that we are proposing must be overcome in virtually all human cancers. The project builds on our previous findings that there is elevated phospholipase D (PLD) activity in many human cancer cells and that suppression of PLD activity in these cells results in apoptotic cell death. Targeting the PLD-mTOR signals in cancer cells represents a very promising strategy for resurrecting the default cell death programs that are arguably the first line of defense against cancer - and is therefore a fertile area for translational research.

描述（由申请人提供）：默认的细胞凋亡程序已被改编为对抗癌症的第一道防线，并且实际上所有癌细胞都具有激活“生存信号”以抑制细胞凋亡的突变。生存信号传导的中心节点是 mTOR（雷帕霉素的哺乳动物靶标）。 mTOR 响应磷脂酰肌醇 3 激酶 (PI3K) 信号通路介导的信号而被激活。然而，最近发现 mTOR 也成为激活磷脂酶 D (PLD) 信号的目标。 PLD 产生磷脂酸 (PA)，这是一种脂质第二信使，以与雷帕霉素竞争的方式直接与 mTOR 相互作用，而 PA 是 mTOR 激活所必需的。重要的是，PLD 活性在几种类型的人类癌症中升高。 PLD 活性在许多人类癌细胞中升高，并且是 mTOR 介导的信号所必需的，这些信号对于生存和促进细胞周期进展至关重要。该提案的中心假设是 - 人类癌细胞中 PLD 活性升高可促进通过 G1 晚期“细胞生长检查点”并抑制默认的细胞凋亡程序。我们提出，几乎所有癌细胞都必须激活允许通过该检查点的信号。具体而言，我们建议：1) 确定 PLD-mTOR 信号如何通过拟议的细胞生长检查点影响细胞周期进展； 2) 确定 PLD 生成的 PA 与其他信号输入协同调节 mTORC1 和 mTORC2 的机制； 3) 表征导致人类癌细胞系中 PLD 活性升高的信号，并在体外和体内评估针对这些信号的药理学作用。我们提出，人类癌细胞中的 PLD-mTOR 信号通路代表了癌细胞广泛采用的促进细胞周期进展和抑制默认凋亡程序的策略。这里提出的研究将为合理靶向大量癌症提供一个框架，这些癌症依赖于 G1 细胞周期进展和抑制细胞凋亡的 PLD 活性升高。公共健康相关性：拟议的研究将评估调节人类癌细胞中磷脂酶 D (PLD) 和 mTOR 的细胞内机制，以及这些信号对我们所提出的细胞周期 G1 期“细胞生长检查点”的影响几乎所有人类癌症都必须克服这个问题。该项目建立在我们之前的发现之上，即许多人类癌细胞中磷脂酶 D (PLD) 活性升高，并且抑制这些细胞中的 PLD 活性会导致细胞凋亡。靶向癌细胞中的 PLD-mTOR 信号代表了一种非常有前途的策略，可以恢复默认的细胞死亡程序，这可以说是对抗癌症的第一道防线，因此是转化研究的沃土。