_________________________________________________________________________________________________________________________ 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. _________________________________________________________________________________________________________________________

Public Health Relevance

_________________________________________________________________________________________________________________________ Project-2. Salinomycin's Effects and Binding Target Proteins in Pancreatic Cancer (PI: Dr. Erxi Wu) Project Narrative Pancreatic cancer is a tremendous public health burden as it has the lowest 5-year survival rate among all types of tumors and a median survival rate of less than 6 months. The existence of cancer stem cells is considered to be one of the major causes for pancreatic cancer therapy resistance and pancreatic cancer patients' relapse from therapy. Salinomycin, one of the most widely used coccidiostats, has been found to possess profound efficacy towards cancer stem cells and to overcome multiple drug resistance in cancers. This study will determine salinomycin's binding target proteins and their functions in pancreatic cancer cells as well as the signaling pathways regulated by salinomycin and its binding proteins. The results from this research project will advance our knowledge in understanding of the molecular mechanisms of action of salinomycin and the combination of salinomycin with gemcitabine in pancreatic cancer, yielding new insights and strategies for pancreatic cancer interventions. _________________________________________________________________________________________________________________________

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM109024-01A1
Application #
8813062
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2016-02-04
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
North Dakota State University
Department
Type
DUNS #
803882299
City
Fargo
State
ND
Country
United States
Zip Code
58108
Zheng, Wanli; Yao, Li; Teng, Jun et al. (2018) Lateral Flow Test for Visual Detection of Multiple MicroRNAs. Sens Actuators B Chem 264:320-326
Scott, Andrew J; Walker, Sierra A; Krank, Joshua J et al. (2018) AIF promotes a JNK1-mediated cadherin switch independently of respiratory chain stabilization. J Biol Chem 293:14707-14722
Mohammad, Jiyan; Dhillon, Harsharan; Chikara, Shireen et al. (2018) Piperlongumine potentiates the effects of gemcitabine in in vitro and in vivo human pancreatic cancer models. Oncotarget 9:10457-10469
Chikara, Shireen; Mamidi, Sujan; Sreedasyam, Avinash et al. (2018) Flaxseed Consumption Inhibits Chemically Induced Lung Tumorigenesis and Modulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/J Mice. Cancer Prev Res (Phila) 11:27-37
Ray, Priyanka; Confeld, Matthew; Borowicz, Pawel et al. (2018) PEG-b-poly (carbonate)-derived nanocarrier platform with pH-responsive properties for pancreatic cancer combination therapy. Colloids Surf B Biointerfaces 174:126-135
Quadir, Mohiuddin; Fehse, Susanne; Multhaup, Gerhard et al. (2018) Hyperbranched Polyglycerol Derivatives as Prospective Copper Nanotransporter Candidates. Molecules 23:
Xu, Yi; Pang, Lizhi; Wang, Hongzhi et al. (2018) Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-?-linolenic acid for colon cancer suppression. Redox Biol 21:101085
Karandish, Fataneh; Froberg, James; Borowicz, Pawel et al. (2018) Peptide-targeted, stimuli-responsive polymersomes for delivering a cancer stemness inhibitor to cancer stem cell microtumors. Colloids Surf B Biointerfaces 163:225-235
Guo, Zebin; Zheng, Yafeng; Xu, Hui et al. (2017) Lateral flow test for visual detection of silver (I) based on cytosine-Ag(I)-cytosine interaction in C-rich oligonucleotides. Mikrochim Acta 184:4243-4250
Huang, Yan; Wen, Yongqiang; Baryeh, Kwaku et al. (2017) Lateral flow assay for carbohydrate antigen 19-9 in whole blood by using magnetized carbon nanotubes. Mikrochim Acta 184:4287-4294

Showing the most recent 10 out of 14 publications