Effects of salinomycin and binding target proteins in pancreatic cancer

盐霉素和结合靶蛋白对胰腺癌的影响

• 批准号: 8813062
• 负责人: Erxi Wu
• 金额: $ 23.27万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813062
• 关键词: Antineoplastic Agents; Binding; Binding Proteins; Cancer Center; Cancer Intervention; Cancer Patient; Cancer cell line; Cell Differentiation Induction; Cell Proliferation; Cell Survival; Cells; Data; Diagnosis; Diagnostic; Disease; Dissociation; Drug Design; Gene Expression; Genes; Genetic Transcription; Goals; Human; Immune; Immunoprecipitation; In Vitro; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular Mechanisms of Action; Multi-Drug Resistance; Mus; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pilot Projects; Proteins; Public Health; Publishing; Regimen; Relapse; Reporting; Research; Research Project Grants; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Specimen; Structural Models; Survival Rate; Testing; Therapeutic; Transgenic Mice; Xenograft procedure; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; clinically relevant; cytotoxicity; gemcitabine; in vitro Assay; in vivo; insight; knock-down; mouse model; notch protein; novel; novel anticancer drug; novel therapeutics; nucleolin; overexpression; pancreatic cancer cells; programs; salinomycin; therapeutic target; transcriptional intermediary factor 1; tumor; tumor progression

_________________________________________________________________________________________________________________________ Project-2. Salinomycin's Effects and Binding Target Proteins in Pancreatic Cancer (PI: Dr. Erxi Wu) Project Summary Pancreatic Cancer (PC) is a deadly disease and its 5-year survival rate is approximately 6% due to late diagnoses and therapy resistance. The existence of cancer stem cells (CSCs) in PC is considered as a major cause for PC therapy resistance and PC patients' relapse from therapy. Salinomycin, one of the most widely used coccidiostats, has been found to possess profound efficacy towards CSCs and to overcome multiple drug resistance in cancers. Our preliminary data showed that salinomycin possesses strong cytotoxicity against PC cells. We identified two salinomycin's potential binding targets: transcription intermediary factor-1beta (TIF1¿) and nucleolin (NCL) in PC cells. However, the action mechanism of salinomycin in PC still remains unclear; especially its direct binding targets. In this project, we propose that the inhibitory effects of salinomycin on cancer and CSCs could be due to 1) the reduction of cell proliferation and survival and/or, 2) the induction of cell differentiation. The goal of this proposed study is to determine salinomycin's binding target proteins and their functions in PC as well as the signaling pathways regulated by salinomycin and its binding proteins. We hypothesize that specific target proteins exist in the salinomycin responsive cells and that salinomycin initiates its function via its binding target proteins. Three specific aims will be used to test the hypothesis. Aim 1. To determine the binding target proteins of salinomycin in PC and PC-CSC as well as their clinical relevance using pathological specimens. The direct binding of salinomycin to TIF1b and NCL will be determined using immunoprecipitation and immune-binding approaches. The interaction between salinomycin and its potential targets will be further confirmed by analyzing their association and dissociation profiles. The clinical relevance of TIF1b and NCL will be examined by assessing the correlation of the expression levels of both genes with patients' outcomes. Aim 2. To determine the roles of TIF1¿ and NCL for salinomycin against Gemcitabine resistant PC cells. The effects of salinomycin will be analyzed in vitro and in vivo at various conditions including lack or overexpression of TIF1¿ and/or NCL. The efficacies of salinomycin and the combination with Gemcitabine on PC will be determined using a transgenic mouse model. Aim 3. To dissect the signaling pathways regulated by salinomycin, gemcitabine, their combination, and the binding proteins of salinomycin in PC cells. The effects of salinomycin and its target proteins on the expression of genes in the key pathways in PC progression will be determined using customized RT-PCR array. The identified targets will be further evaluated using multiple strategies. This proposed study will provide new insight into the mechanism of PC therapy resistance and a theoretical basis for the use of salinomycin or combination with Gem as novel anti-PC regimens. _________________________________________________________________________________________________________________________

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