G-Protein Signaling in Pancreatic Cancer

描述(申请人提供)：此R21申请(响应PA-06-303，标题为“胰腺癌的初步研究”)是基于我们最近的发现，溶血磷脂酸(LPA)是一种简单的生物活性甘油磷脂，刺激其同源G蛋白偶联受体(GPCRs)，除了反式激活c-Met外，还可以激活胰腺癌细胞中的致癌细胞生长和细胞迁移。LPA是LPA受体家族(LPAR)的配体，在卵巢癌和胰腺癌的发生发展中具有重要的生物学意义。最近的研究表明，LPA可以刺激胰腺癌细胞的迁移和c-Met的反式激活，c-Met的反式激活被认为是许多癌细胞系运动的关键因素。然而，人们对潜在的机制知之甚少。在这种背景下，我们最近的研究发现，gep癌基因G介导的受体酪氨酸激酶的反式激活和细胞运动具有重要意义。基于这些发现，我们假设一种特定的LPA受体通过不同的异三聚体G蛋白和下游的小GTP酶刺激胰腺癌的进展。这一假设将在以下具体目标下进行检验：AIM-1。明确参与c-Met反式激活、胰腺癌细胞迁移和侵袭的LPA受体(S)。使用针对每个受体的siRNA，我们将使用一组由BcPC3、Dan G.MDAPANC-28和Mia Paca-2细胞组成的癌细胞系来定义介导c-Met反式激活和胰腺癌细胞系侵袭性迁移的受体。AIM-2。定义异三聚体G蛋白，它将LPAR偶联到参与c-Met反式激活、迁移和侵袭的细胞反应中。LPAR已被证明通过由各自LPAR(在先前的目的中确定)的G突变体定义的异三聚体G蛋白将其信息传递到细胞内效应器。除了确定与胰腺癌进展有关的新的病因学因素外，这些研究的结果有望确定治疗该疾病的新的治疗靶点。这些研究将确定和表征与胰腺癌发生和发展有关的新的病因学因素。此外，这些研究的结果有望确定胰腺癌的新诊断、预后和治疗靶点。

DESCRIPTION (provided by applicant): This R21 application (in response to PA-06-303, titled "Pilot Studies in Pancreatic Cancer") is based on our recent finding that lysophosphatidic acid (LPA), a simple, bioactive glycerophospholipid that stimulates its cognate G protein coupled receptors (GPCRs) can activate both oncogenic cell growth and cell migration in addition to transactivating c-Met in pancreatic cancer cells. LPA, the ligand for a family of LPA-receptors (LPARs), has emerged as a factor of biological importance in the progression of ovarian as well as pancreatic cancers. Recent studies have shown that LPA can stimulate pancreatic cancer cell migration as well as the transactivation of c-Met, which is known to be critically involved in the motility of many cancer cell lines. However, relatively little is known about underlying mechanisms. In this context, our recent findings that the gep oncogene G mediated transactivation of receptor tyrosine kinases and cell movement are of great significance. Based on these findings, we hypothesize that a specific LPA-receptor stimulates the progression of pancreatic cancer via distinct heterotrimeric G proteins and the downstream small GTPases. This hypothesis will be tested under the following specific aims: Aim-1. Define the LPA-receptor(s) involved in the transactivation of c-Met, migration, and invasion of pancreatic cancer cells. Using siRNA specific to each of these receptors, we will define the receptor that mediates the transactivation of c-Met and invasive migration of pancreatic cancer cell lines using a panel of cancer cell lines consisting of BcPC3, Dan G. MDAPanc-28, and Mia PaCa-2 cells. Aim-2. Define the heterotrimeric G protein that couples LPARs to cellular responses involved in the transactivation of c-Met, migration, and invasion. LPARs have been shown to transmit their messages via the heterotrimeric G proteins defined by the G mutants of the respective LPAR (identified in the previous aim) to the intracellular effectors. In addition to characterizing novel etiological factors involved in the progression of pancreatic cancer, the outcome of these studies is expected to identify novel therapeutic targets for the treatment of the disease. These studies will identify and characterize novel etiological factors involved in the genesis and progression of pancreatic cancer. In addition, the outcome of these studies is expected to identify novel diagnostic, prognostic and therapeutic targets for pancreatic cancer.