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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 06, 2015 |
| Title |
Gene expression profiling of mouse salivary gland cancer stem cells treated with Wnt inhibitors |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
To analyze whether Wnt inhibitors LF3 and ICG-001 have similar influence on the gene expression of mouse salivary gland cancer stem cells
Wnt/β-catenin signaling is a system that is essential for embryogenesis and tissue homeostasis which has been highly conserved through evolution. A deregulation of Wnt/β-catenin signals can initiate and promote human cancers, specifically of the colon, head and neck. As such, Wnt/β-catenin signaling represents an attractive target for cancer therapy. So far, however, no rationally developed compound targeting Wnt signaling has found clinical use. The interaction between β-catenin and TCF4 is necessary in the transduction of the signal; here we performed a High-Throughput-Screening (HTS) using AlphaScreen and ELISA techniques to identify small molecules that specifically disrupt this interaction. We identified compound LF3, a 4-thioureido-benzenesulfonamide derivative, as a robust inhibitor of β-catenin/TCF4 interactions and thus a good starting point for drug discovery, as suggested by Lipinski's “rule of five.” LF3 inhibited Wnt/β-catenin signaling in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. Medicinal chemistry identified an essential core structure and residues that could not be modified in LF3. Compound LF3 inhibited a number of features of cancer cells related to Wnt signaling, including high cell motility in Boyden chamber assays, hyperproliferation through induction of cell cycle arrest at the G1 phase, and the overexpression of key Wnt target genes. LF3 does not cause apoptosis or cell death or interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as demonstrated by examination of sphere formation of colon and head and neck cancer stem cells in serum-free, non-attached conditions. LF3 also reduced tumor growth and induced differentiation in colon tumors in mouse xenografts. LF3 is thus a specific inhibitor of canonical Wnt signaling with a significant potential for further development for preclinical and clinical studies in cancer treatment.
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| Overall design |
Mouse salivary gland cancer stem cells were treated with LF3 and ICG-001 for 24 h and harvested in trizol for total RNA isolation.
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| Contributor(s) |
Fang L, Zhu Q |
| Citation(s) |
26645562 |
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| Submission date |
Oct 05, 2015 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Liang Fang |
| Organization name |
Max Delbrück Center for Molecular Medicine
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| Lab |
Lab of Walter Birchmeier
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| Street address |
Robert-Rössle-Str. 10
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| City |
Berlin |
| ZIP/Postal code |
13125 |
| Country |
Germany |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA297782 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE73732_RAW.tar |
13.7 Mb |
(http)(custom) |
TAR (of IDAT) |
| GSE73732_non_normalized.txt.gz |
942.8 Kb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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