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“胰腺癌的试点研究”）是基于我们最近的发现，溶血磷脂酸（LPA），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（gpcr），除了在胰腺癌细胞中转激活c-Met外，还可以激活致癌细胞生长和细胞迁移。LPA是LPA受体家族（LPARs）的配体，在卵巢癌和胰腺癌的进展中已成为一个重要的生物学因素。最近的研究表明，LPA可以刺激胰腺癌细胞的迁移以及c-Met的反激活，而c-Met在许多癌细胞系的运动中起着关键的作用。然而，人们对其潜在机制知之甚少。在此背景下，我们最近发现gep癌基因G介导酪氨酸激酶受体的转激活和细胞运动具有重要意义。基于这些发现，我们假设特定的lpa受体通过不同的异源三聚体G蛋白和下游小gtpase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。明确参与胰腺癌细胞c-Met反活化、迁移和侵袭的lpa受体。使用每种受体特异性的siRNA，我们将使用由BcPC3、Dan G. mdapac -28和Mia PaCa-2细胞组成的一组癌细胞系，确定介导c-Met反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，将LPARs偶联到参与c-Met转激活、迁移和侵袭的细胞反应中。LPAR通过各自LPAR的G突变体定义的异源三聚体G蛋白（在前面的目标中确定）将它们的信息传递给细胞内效应器。除了描述胰腺癌进展中涉及的新病因外，这些研究的结果有望确定治疗该疾病的新治疗靶点。这些研究将确定和描述胰腺癌发生和发展的新病因因素。此外，这些研究的结果有望确定胰腺癌的新的诊断、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.