Role of Protein Kinase D in Pancreatic Cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)可能是已知的最具侵袭性的癌症形式，总体5年生存率最低。由于PDAC对传统化疗药物具有极强的耐药性，因此迫切需要寻找新的分子靶点。蛋白激酶D(PKD)此前被认为是一种在胰腺癌中过表达的激酶，并被证明在胰腺癌细胞系中促进细胞增殖和防止凋亡。目前对PDAC中调节这些过程的许多信号通路进行了研究，以开发分子疗法。然而，到目前为止，针对许多相关的信号分子在临床试验中未能奏效。K-ras基因突变或慢性胰腺炎导致的ROS的产生被认为是PDAC发生发展的关键步骤。我们以前已经证明，PKD是氧化应激的传感器，我们的初步数据表明，ROS激活的PKD在胰腺癌的信号转导中起着关键作用。PDAC的另一个特点是对常见化疗药物高度耐药。我们的初步数据进一步表明，PKD也可能与常见化疗药物的耐药有关。因此，我们的假设是，PKD在传递ROS和K-ras介导的信号从而导致胰腺癌细胞转化中起着至关重要的作用。我们进一步假设，由该途径激活的PKD通过抑制凋亡途径积极地参与了化疗药物的耐药。为了测试这一点，我们将：评估ROS激活的PKD在PDAC细胞转化信号中的作用(目标1)；确定K-ras或ROS激活的PKD是否有助于PDAC的化疗耐药(目标2)；以及评估氧化应激激活的PKD的潜在作用是胰腺癌的致癌标记物(目标3)。因此，为了有效地利用化疗来防止胰腺癌的扩散，迫切需要寻找新的分子靶点，既介导肿瘤细胞的转化，又介导对化疗药物的耐药性。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，并导致调节细胞生存、增殖和对化疗耐药的信号事件的激活。

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.