Role of Protein Kinase D in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）可能是已知最具侵袭性的癌症，5年总生存率最低。由于PDAC对常规化疗具有极强的抗性，因此迫切需要鉴定新的分子靶点。蛋白激酶D（PKD）以前被认为是胰腺癌中过表达的激酶，并显示出在胰腺癌细胞系中增加细胞增殖和防止细胞凋亡。目前正在研究调节PDAC中这些过程的许多信号通路以开发分子治疗剂。然而，迄今为止，靶向许多相关的信号分子在临床试验中未能有效。反应性氧簇（ROS）的产生，无论是在响应K-ras突变或作为慢性胰腺炎的结果已被牵连作为一个关键步骤的发展PDAC。我们之前已经表明PKD是氧化应激的传感器，我们的初步数据表明ROS激活的PKD是胰腺癌中转化信号级联的关键参与者。PDAC的另一个特征是它们对常见的化疗剂具有高度抗性。我们的初步数据进一步表明，PKD也可能参与介导对常见化疗药物的耐药性。因此，我们假设PKD在传递活性氧（ROS）和K-ras介导的信号传导中起着至关重要的作用，导致胰腺癌细胞转化。我们进一步假设，PKD，激活这一途径积极有助于通过抑制凋亡途径化疗药物的耐药性。为了测试这一点，我们将：评估ROS激活的PKD在PDAC细胞中转化信号传导中的作用（目标1）;确定K-ras或ROS激活的PKD是否有助于PDAC中的化疗药物抗性（目标2）;以及评估氧化应激激活的PKD作为胰腺癌的致癌标志物的潜在作用（目标3）。胰腺癌细胞是高度增殖的，并且对大多数常规化疗药物具有抗性。因此，为了有效地使用化疗来防止胰腺癌扩散，迫切需要鉴定新的分子靶标，介导肿瘤细胞转化和对化疗药物的抗性。我们认为蛋白激酶D（PKD）是这些关键蛋白之一，因为胰腺癌细胞中的PKD被K-ras和氧化应激激活，并且它导致调节细胞存活、增殖和化疗抗性的信号事件的激活。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is probably the most aggressive form of cancer known, with the lowest overall 5-year survival rate. Since PDAC is extremely resistant to conventional chemotherapies there is a desperate need to identify new molecular targets. Protein Kinase D (PKD) previously was recognized as a kinase overexpressed in pancreatic cancer and was shown to increase cell proliferation and prevent apoptosis in pancreatic cancer cell lines. Many of the signaling pathways regulating these processes in PDAC are currently investigated to develop molecular therapeutics. However, to date, targeting many of the involved signaling molecules failed to be effective in clinical trials. The generation of reactive oxygen species (ROS) either in response to K-ras mutations or as a consequence of chronic pancreatitis has been implicated as a crucial step in the development of PDAC. We have shown previously that PKD is a sensor for oxidative stress and our preliminary data suggests that ROS-activated PKD is a key player in transforming signaling cascades in pancreatic cancer. An additional feature of PDACs is that they are highly resistant to common chemotherapeutic agents. Our preliminary data further suggests that PKD may also be implicated in mediating resistance to common chemotherapeutics. Therefore, it is our hypothesis that PKD plays an crucial role in relaying reactive oxygen species (ROS)- and K-ras-mediated signaling, resulting in pancreatic cancer cell transformation. We further hypothesize that PKD, activated by this pathway actively contributes to resistance to chemotherapeutics by inhibiting apoptotic pathways. To test this we will: Assess the role of ROS-activated PKD in transformed signaling in PDAC cells (Aim 1); Determine if K-ras or ROS-activated PKD contributes to chemotherapeutica-resistance in PDAC (Aim 2); and Evaluate the Potential role of oxidative stress-activated PKD is an oncogenic marker for pancreatic cancer (Aim 3).PUBLIC HEALTH RELEVANCE: Pancreatic cancer cells are highly proliferative and resistant to most of the conventional chemotherapeutic drugs. Therefore, to effectively use chemotherapy to prevent pancreatic cancer from spreading, there is a dire need to identify new molecular targets, mediating both tumor cell transformation and resistance to chemotherapeutics. We propose that Protein Kinase D (PKD) is one of these key proteins because PKD in pancreatic cancer cells is activated by K-ras and oxidative stress, and it leads to activation of signaling events regulating cell survival, proliferation and resistance to chemotherapy.