Data from ASNA-1 Activity Modulates Sensitivity to Cisplatin

Abstract

<div>Abstract<p>Cancer can be cured by platinum-based chemotherapy, but resistance is a major cause of treatment failure. Here we present the nematode <i>Caenorhabditis elegans</i> as a model to study interactions between the platinum drug cisplatin and signaling pathways <i>in vivo</i>. Null mutation in a single gene, <i>asna-1</i>, 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 <i>asna-1</i> mutants. These findings provide a functional insight into ASNA-1, demonstrate that <i>C. elegans</i> can be used to characterize cisplatin resistance mechanisms, and suggest that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin. <i>Cancer Res; 70(24); 10321–8. ©2010 AACR.</i></p></div>