| ASNA-1 activity modulates sensitivity to cisplatin. | |
| | |
MedLine Citation:
|
PMID: 20966125 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Cancer can be cured by platinum-based chemotherapy, but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutation in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologues, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild-type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms, and suggest that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin. |
| | |
Authors:
|
Oskar Hemmingsson; Gautam Kao; Maria Still; Peter Naredi |
Related Documents
:
|
15031295 - Primary and essential role of the adaptor protein aps for recruitment of both c-cbl and... 11574405 - Phosphorylation-dependent nucleocytoplasmic shuttling of pancreatic duodenal homeobox-1. 10974195 - Protein tyrosine phosphatase-1b in diabetes. 8663315 - Analysis of the signaling pathway involved in the regulation of hexokinase ii gene tran... 17054605 - Asian mody: are we missing an important diagnosis? 12663085 - Glycation--a sweet tempter for neuronal death. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-21 |
Journal Detail:
|
Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Dec |
Date Detail:
|
Created Date: 2010-12-16 Completed Date: 2011-01-20 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
|
Languages: eng Pagination: 10321-8 Citation Subset: IM |
Copyright Information:
|
©2010 AACR. |
Affiliation:
|
Division of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Apoptosis / drug effects, genetics Arsenite Transporting ATPases / genetics* Caenorhabditis elegans / genetics, metabolism Caenorhabditis elegans Proteins / genetics* Cell Growth Processes / drug effects, genetics Cisplatin / pharmacology* Humans Insulin / metabolism Mutagenesis, Site-Directed Signal Transduction / drug effects |
| Chemical | |
Reg. No./Substance:
|
0/ASNA1 protein, human; 0/Caenorhabditis elegans Proteins; 11061-68-0/Insulin; 15663-27-1/Cisplatin; EC 3.6.3.16/ASNA-1 protein, C elegans; EC 3.6.3.16/Arsenite Transporting ATPases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Thrombotic microangiopathy and peritubular capillary C4d expression in renal allograft biopsies.
Next Document: XMRV: a new virus in prostate cancer?