ASNA-1 activity modulates sensitivity to cisplatin.
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.
Division of Surgery, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.
Oskar
O
Hemmingsson
Gautam
G
Kao
Maria
M
Still
Peter
P
Naredi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053501:Arsenite Transporting ATPases / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D015398:Signal Transduction / Q000187:drug effects
D029742:Caenorhabditis elegans Proteins; C489667:GET3 protein, human; D007328:Insulin; C518267:ASNA-1 protein, C elegans; D053501:Arsenite Transporting ATPases; D002945:Cisplatin