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Series GSE89766 Query DataSets for GSE89766
Status Public on Feb 16, 2018
Title Disruption of autophagic degradation with ROC-325 antagonizes renal cell carcinoma pathogenesis
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Autophagy plays important roles in malignant pathogenesis and drug resistance. We used medicinal chemistry approaches to generate a series of novel agents that inhibit autophagic degradation. ROC-325 was selected as a lead compound for further evaluation. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325 in preclinical models of renal cell carcinoma (RCC). ROC-325 exhibited superior in vitro anticancer effects than the existing autophagy inhibitor hydroxychloroquine in 12 different tumor models with diverse genetic backgrounds. Focused studies of the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug treatment induced hallmark characteristics of autophagy inhibition including accumulation of autophagosomes with undegraded cargo, lysosomal deacidification, p62 stabilization, and disruption of autophagic flux. Subsequent experiments showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent manner, induced apoptosis, and exhibited favorable selectivity. Oral administration of ROC-325 to mice bearing 786-0 RCC xenografts was well tolerated, significantly more effective at inhibiting tumor progression than HCQ, and inhibited autophagy in vivo.
We used microarrays to determine gene expression changes following 24 h treatment with ROC-325 in RCC cell lines and identified differentially expressed genes.
 
Overall design Microarray analyses were performed on two RCC cell lines, 786-O and A498. Cells were wither untreated (Control) or treated with 5 uM ROC-325 for 24 hours. Each sample was run in triplicate for a total of 6 samples per cell lines.
 
Contributor(s) Nawrocki ST, Carew JS
Citation(s) 27881580
Submission date Nov 10, 2016
Last update date Jul 26, 2018
Contact name Jennifer Carew
E-mail(s) jcarew@email.arizona.edu
Organization name USA
Street address University of Arizona Cancer Center, 1515 N. Campbell Ave
City Tucson
State/province Arizona
ZIP/Postal code 85724
Country USA
 
Platforms (1)
GPL6244 [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version]
Samples (12)
GSM2388397 786-O Control, biological rep 1
GSM2388398 786-O Control, biological rep 2
GSM2388399 786-O Control, biological rep 3
Relations
BioProject PRJNA353118

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Supplementary file Size Download File type/resource
GSE89766_RAW.tar 53.8 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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