Deciphering the Role of eIF5A/PEAK1 Pathway in Pancreatic Cancer

解读 eIF5A/PEAK1 通路在胰腺癌中的作用

• 批准号: 8593717
• 负责人: KEN FUJIMURA
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593717
• 关键词: Address; Adenocarcinoma Cell; Amino Acids; Animal Model; Antineoplastic Agents; Apoptosis; Biochemical; Biological Assay; Biological Markers; Cancer Etiology; Cause of Death; Cell Cycle Progression; Cell Line; Cell Proliferation; Cells; Cessation of life; Clinical; Communities; Data; Detection; Development; Disease; Eukaryotic Initiation Factors; Genetic; Genetic Engineering; Goals; Growth; In Vitro; Lead; Lysine; Malignant neoplasm of pancreas; Mediating; Messenger RNA; Methods; Modeling; Neoplasm Metastasis; Nude Mice; Onset of illness; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphotransferases; Post-Translational Protein Processing; Protein Biosynthesis; Proteins; Pseudopodia; Reaction; Regulation; Repression; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Spermidine; Survival Rate; Testing; Therapeutic; Tissues; Treatment Protocols; Tumorigenicity; Up-Regulation; Validation; anticancer research; base; cancer type; chemotherapy; clinically relevant; deoxyhypusine monooxygenase; deoxyhypusine synthase; design; gemcitabine; hypusine; implantation; in vivo; in vivo Model; insight; killings; mouse model; new therapeutic target; novel; novel therapeutics; pre-clinical; protein transport; public health relevance; therapeutic target; tissue culture; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the leading causes of death. This is mainly due to the lack of relevant detection methods and therapeutic targets, as well as therapy resistance. Gemcitabine, the current first-line treatment, is effective only in limited percentage f patients and typically encounters the problem of resistance. In this proposal, we propose to address these issues by focusing on the eukaryotic translation initiation factor 5A (eIF5A), a candidate biomarker and a chemotherapeutic target we identified through our preliminary studies. Our data show that eIF5A and activated form of this protein is upregulated in the majority of PDAC patient tissues from the onset of the disease, and inhibition of eIF5A activity efficiently kills PDAC cells in vitro. We also provide evidence that eIF5A regulates the expression of PEAK1 (pseudopodium atypical enriched kinase 1), a catalytically active kinase that we recently demonstrated as a signaling hub in PDAC cells critical for their survival and therapy resistance. Importantly, our data suggest that eIF5A hypusination and PEAK1 expression may constitute a compensatory mechanism responsible for resistance to gemcitabine. In this proposal, we propose to extensively study the mechanism of eIF5A regulation on PDAC growth and PEAK1 expression using both in vitro and in vivo models. First, using in vitro tissue culture models, we will determine how eIF5A regulates proliferation, cell cycle progression, apoptosis and tumorigenicity of PDAC cells and also determine whether PEAK1 is the downstream effector of eIF5A in PDAC growth. Subsequently, we will validate our in vitro results in vivo, using clinically relevant orthotopic implantation nude mouse models of pancreatic cancer. Completion of our studies will uncover a novel mechanism of PDAC growth and establish eIF5A as a novel therapeutic target, which will eventually address the need for a new, effective and feasible treatment for this deadly, difficult-to-treat disease.

描述（由申请方提供）：胰腺导管腺癌（PDAC）是胰腺癌最常见的形式，仍然是死亡的主要原因之一。这主要是由于缺乏相关的检测方法和治疗靶点，以及治疗耐药性。吉西他滨是目前的一线治疗药物，仅在有限比例的患者中有效，并且通常遇到耐药问题。在这项提案中，我们建议通过关注真核生物翻译起始因子5A（eIF5A）来解决这些问题，eIF5A是我们通过初步研究确定的候选生物标志物和化疗靶点。我们的数据显示，eIF5A和该蛋白的活化形式在大多数PDAC患者组织中从疾病开始上调，并且抑制eIF5A活性在体外有效地杀死PDAC细胞。我们还提供了eIF5A调节PEAK1（伪足非典型富集激酶1）表达的证据，PEAK1是一种催化活性激酶，我们最近证明它是PDAC细胞中对其生存和治疗抗性至关重要的信号传导中心。重要的是，我们的数据表明，eIF5A hypusination和PEAK1表达可能构成了一种补偿机制，负责耐吉西他滨。在这个提议中，我们建议使用体外和体内模型广泛研究eIF5A对PDAC生长和PEAK 1表达的调节机制。首先，使用体外组织培养模型，我们将确定eIF5A如何调节PDAC细胞的增殖、细胞周期进程、凋亡和致瘤性，并确定PEAK1是否是eIF5A在PDAC生长中的下游效应子。随后，我们将使用临床相关的胰腺癌原位移植裸鼠模型在体内验证我们的体外结果。我们研究的完成将揭示PDAC生长的新机制，并将eIF5A确立为新的治疗靶点，这将最终解决对这种致命的、难以治疗的疾病的新的、有效的和可行的治疗的需求。