| PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition. | |
| | |
MedLine Citation:
|
PMID: 19281821 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key "executioner" caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds. |
| | |
Authors:
|
Quinn P Peterson; David R Goode; Diana C West; Kara N Ramsey; Joy J Y Lee; Paul J Hergenrother |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-03-10 |
Journal Detail:
|
Title: Journal of molecular biology Volume: 388 ISSN: 1089-8638 ISO Abbreviation: J. Mol. Biol. Publication Date: 2009 Apr |
Date Detail:
|
Created Date: 2009-04-07 Completed Date: 2009-05-19 Revised Date: 2011-08-01 |
Medline Journal Info:
|
Nlm Unique ID: 2985088R Medline TA: J Mol Biol Country: England |
Other Details:
|
Languages: eng Pagination: 144-58 Citation Subset: IM |
Affiliation:
|
Department of Biochemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL 61801, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Caspase 3
/
antagonists & inhibitors,
metabolism* Caspase 7 / antagonists & inhibitors, metabolism Cell Line, Tumor Dual Specificity Phosphatase 2 / metabolism* Enzyme Precursors / metabolism* Humans Zinc / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
|
1 T32 GM070421/GM/NIGMS NIH HHS; 3F31CA130138-01S1/CA/NCI NIH HHS; R01 CA120439-02/CA/NCI NIH HHS; R01-CA120439/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Enzyme Precursors; 7440-66-6/Zinc; EC 3.1.3.48/Dual Specificity Phosphatase 2; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Desmin and vimentin intermediate filament networks: their viscoelastic properties investigated by me...
Next Document: A deoxyribozyme, Sero1C, uses light and serotonin to repair diverse pyrimidine dimers in DNA.