ASNA-1 activity modulates sensitivity to cisplatin
2010 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 24, 10321-10328 p.Article in journal (Refereed) Published
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 mutations 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 homologs, 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 propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.
Place, publisher, year, edition, pages
American Association for Cancer Research , 2010. Vol. 70, no 24, 10321-10328 p.
ASNA1, cisplatin, C. elegans, Drug resistance, arsenite
Cancer and Oncology Pharmaceutical Sciences Cell Biology
Research subject Surgery; Oncology
IdentifiersURN: urn:nbn:se:umu:diva-37629DOI: 10.1158/0008-5472.CAN-10-1548ISI: 000285334200033PubMedID: 20966125OAI: oai:DiVA.org:umu-37629DiVA: diva2:369453