Role of phospholipase D in tumorigenesis

磷脂酶 D 在肿瘤发生中的作用

• 批准号: 7144110
• 负责人: DAVID A FOSTER
• 金额: $ 19.76万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144110
• 关键词: apoptosis; breast neoplasms; cell migration; human; metastasis; neoplasm /cancer; neoplastic cell; phospholipase D; role

DESCRIPTION (provided by applicant): Elevated phospholipase D (PLD) activity has been reported in several types of human cancer including breast, kidney, colon and gastric cancer. Recent work has revealed that elevated PLD activity in human breast cancer cells can suppress apoptosis and promote cell migration - two critical steps in progression to a malignant cancer. The survival and migration signals generated by PLD are mediated - at least in part - by mTOR (the mammalian target of rapamycin), which has been widely implicated in cancer survival signals. While it is clear that PLD is capable of contributing to tumorigenesis and that PLD activity is elevated in a large number of human cancers, it is not known how and in what context elevated PLD activity contributes to the transformation of human cells or tumorigenesis in an animal. There is also much to be learned about the signaling pathways that activate PLD in human cancer cells. The Central Hypothesis of the proposal is that: PLD generates signals that suppress apoptosis and enhance cell migration in human cancer cells. Specifically, we propose to: 1) Characterize signals regulating PLD activity in human cancer cell lines and to evaluate targeting these signals pharmacologically both in vitro and in vivo; 2) Investigate a role for PLD survival signals in cell migration and metastasis; and 3) Evaluate the ability of PLD to cooperate with oncogenes to transform human cells in culture and to stimulate cell migration. The ability of PLD to both suppress apoptosis and enhance cell migration makes PLD an ideal target for the development of therapeutic strategies. As the era of molecular medicine and pathology evolves and individual tumors are examined at the molecular level, elevated PLD activity could be easily determined and the signals generated by PLD activity could then be targeted specifically. The studies proposed here will provide a conceptual framework for rational targeting of the apparent large number of human cancers with elevated PLD activity.

描述（由申请人提供）：据报道，包括乳腺癌，肾脏，结肠癌和胃癌在内的几种类型的人类癌症，磷脂酶D（PLD）活性升高。最近的工作表明，人类乳腺癌细胞中的PLD活性升高可以抑制细胞凋亡并促进细胞迁移 - 进展为恶性癌的两个关键步骤。 PLD产生的生存和迁移信号至少是由MTOR（雷帕霉素的哺乳动物靶标）介导的，该信号已广泛与癌症存活信号有关。虽然很明显，PLD能够有助于肿瘤发生，并且PLD活性在大量人类癌症中升高，但尚不清楚升高PLD活性如何以及在哪些情况下有助于人类细胞的转化或动物中的肿瘤发生。关于激活人类癌细胞中PLD的信号传导途径还有很多值得了解的知识。该提案的中心假设是：PLD产生抑制凋亡并增强人类癌细胞中细胞迁移的信号。具体而言，我们建议：1）表征调节人类癌细胞系中PLD活性的信号，并评估靶向这些信号在体外和体内的药理； 2）研究PLD生存信号在细胞迁移和转移中的作用； 3）评估PLD与Oncogenes合作转化培养和刺激细胞迁移的能力。 PLD既抑制细胞凋亡又增强细胞迁移的能力使PLD成为发展治疗策略的理想目标。随着分子医学和病理的时代在分子水平上研究和单个肿瘤的发展，可以轻松确定PLD活性升高，并且可以专门针对PLD活性产生的信号。这里提出的研究将为合理靶向具有PLD活性升高的人类癌症的合理靶向提供一个概念框架。