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| Status |
Public on Apr 29, 2008 |
| Title |
Argyrin A is a p27 stabilizing drug with potent antiproliferative activity in vivo |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Reduction in the cellular levels of the cyclin kinase inhibitor p27kip1 are frequently found in many human cancers and correlate directly with patient prognosis. Specifically ubiquitin dependent proteasomal turnover has been shown to cause reduced p27 expression in many human cancers. We recently demonstated that expression of a stabilized version of p27kip1 (p27kip1T187A) in a genetically modified mouse significantly reduced the number of intestinal adenomatous polyps which progressed to invasive carcinomas. Based on this work we set out to identify compounds which lead to a re-expression of p27 in cancer tissues. In this work we identify Argyrin A a compound derived from myxobacterium archangium gephyra as a potent inducer of p27kip1 expression. Argyrin A induces apoptosis in human colon cancer xenografts and tumor vasculature in vivo leading to a profound reduction in tumor size at well tolerated levels. Argyrin A functions are strictly dependent on the expression of p27kip1 as neither tumor cells nor endothelial cells which do not express p27kip1 respond to this compound. Surprisingly the molecular mechanism by which Argyrin A exerts its p27 dependent biological function is through a potent inhibition of the 20S proteasome.
Keywords: protasome inhibitor, time course, MCF7 cells, genome wide gene expression response, siRNA
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| Overall design |
MCF7 cells were incubated with proteasome inhibitors bortezomib or Argyrin A or proteasome activity was reduced by treatment with siRNA against proteasomal subunits and gene expression profiles were determined at different timepoints thereafter.
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| Contributor(s) |
Geffers R, Malek NP |
| Citation(s) |
18598941 |
| Submission date |
Jul 23, 2007 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Robert Geffers |
| E-mail(s) |
robert.geffers@helmholtz-hzi.de
|
| Phone |
+49 531-6181-3058
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| Organization name |
HCI - Helmholtz Centre for Infection Research
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| Department |
Dep. Molecular Bacteriology
|
| Lab |
Genome Analytics
|
| Street address |
Inhoffenstr. 7
|
| City |
Braunschweig |
| ZIP/Postal code |
38124 |
| Country |
Germany |
| |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA101709 |
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