G-Protein Signaling in Pancreatic Cancer

描述（由申请人提供）：该R21申请（响应PA-06-303，标题为“胰腺癌中的初步研究”）基于我们最近的发现，即溶血磷脂酸（LPA），一种简单的生物活性甘油磷脂，可刺激其同源G蛋白偶联受体（GPCR），除反式激活胰腺癌细胞中的c-Met外，还可激活致癌细胞生长和细胞迁移。LPA是LPA受体（LPAR）家族的配体，已成为卵巢癌和胰腺癌进展中具有生物学重要性的因素。最近的研究表明，LPA可以刺激胰腺癌细胞迁移以及c-Met的反式激活，c-Met已知与许多癌细胞系的运动性密切相关。然而，对潜在机制知之甚少。在这种情况下，我们最近的发现，gep癌基因G介导的受体酪氨酸激酶和细胞运动的反式激活具有重要意义。基于这些发现，我们推测，一个特定的LPA受体刺激胰腺癌的进展，通过不同的异源三聚体G蛋白和下游的小GTP酶。将在以下具体目标下检验这一假设：目标1。定义参与胰腺癌细胞c-Met反式激活、迁移和侵袭的LPA受体。使用对这些受体中的每一种特异性的siRNA，我们将使用由BcPC 3、Dan G. MDAPanc-28和Mia PaCa-2细胞。目标二定义异源三聚体G蛋白，该蛋白将LPAR偶联至参与c-Met反式激活、迁移和侵袭的细胞反应。LPAR已被证明通过异源三聚体G蛋白将其信息传递到细胞内效应物，所述异源三聚体G蛋白由相应LPAR的G突变体（在先前的目的中鉴定）定义。除了表征胰腺癌进展中涉及的新病因因素外，这些研究的结果预计还将确定治疗该疾病的新治疗靶点。这些研究将确定和表征参与胰腺癌发生和发展的新病因学因素。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.