Role of phospholipase D in tumorigenesis

描述(申请人提供)：磷脂酶D(PLD)活性升高已在几种类型的人类癌症中被报道，包括乳腺癌、肾癌、结肠癌和胃癌。最近的研究表明，人类乳腺癌细胞中PLD活性的升高可以抑制细胞凋亡和促进细胞迁移--这是发展为恶性肿瘤的两个关键步骤。PLD产生的生存和迁移信号至少部分是由mTOR(雷帕霉素的哺乳动物靶点)介导的，mTOR被广泛参与癌症生存信号。虽然PLD显然能够促进肿瘤的发生，并且PLD活性在大量人类癌症中升高，但目前尚不清楚PLD活性升高如何以及在何种背景下有助于人类细胞的转化或动物的肿瘤形成。关于激活人类癌细胞中PLD的信号通路，也有很多需要了解。该提议的中心假设是：PLD产生抑制人类癌细胞凋亡和促进细胞迁移的信号。具体地说，我们建议：1)表征调控PLD活性的信号，并在体外和体内评估针对这些信号的药理学；2)研究PLD生存信号在细胞迁移和转移中的作用；以及3)评估PLD与癌基因合作在培养中转化人类细胞和刺激细胞迁移的能力。PLD抑制细胞凋亡和促进细胞迁移的能力使PLD成为治疗策略发展的理想靶点。随着分子医学和病理学时代的发展，在分子水平上对单个肿瘤进行检查，可以很容易地确定PLD活性的升高，然后可以针对PLD活性产生的信号进行特定的靶向。这里提出的研究将为合理靶向PLD活性升高的大量人类癌症提供一个概念性框架。

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.