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）：磷脂酶D （PLD）活性升高已被报道在几种人类癌症中，包括乳腺癌、肾癌、结肠癌和胃癌。最近的研究表明，人乳腺癌细胞中PLD活性的升高可以抑制细胞凋亡和促进细胞迁移，这是恶性肿瘤发展的两个关键步骤。PLD产生的存活和迁移信号至少部分由mTOR（雷帕霉素的哺乳动物靶点）介导，mTOR在癌症存活信号中广泛存在。虽然很明显PLD能够促进肿瘤发生，并且PLD活性在许多人类癌症中升高，但尚不清楚PLD活性升高如何以及在什么情况下促进人类细胞的转化或动物的肿瘤发生。关于激活人类癌细胞中PLD的信号通路也有很多需要了解的。该提案的中心假设是：PLD在人类癌细胞中产生抑制凋亡和增强细胞迁移的信号。具体而言，我们建议：1)表征人类癌细胞系中调节PLD活性的信号，并在体外和体内对这些信号进行药理学评价；2)研究PLD存活信号在细胞迁移和转移中的作用；3)评估PLD与癌基因合作转化培养的人类细胞和刺激细胞迁移的能力。PLD抑制细胞凋亡和增强细胞迁移的能力使PLD成为开发治疗策略的理想靶点。随着分子医学和病理学时代的发展以及个体肿瘤在分子水平上的检测，可以很容易地确定PLD活性的升高，从而可以特异性地靶向PLD活性产生的信号。这里提出的研究将为合理靶向大量PLD活性升高的人类癌症提供一个概念框架。