ASNA-1 activity modulates sensitivity to cisplatin

Cancer Res. 2010 Dec 15;70(24):10321-8. doi: 10.1158/0008-5472.CAN-10-1548. Epub 2010 Oct 21.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Arsenite Transporting ATPases / genetics*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / genetics
  • Cisplatin / pharmacology*
  • Humans
  • Insulin / metabolism
  • Mutagenesis, Site-Directed
  • Signal Transduction / drug effects

Substances

  • Caenorhabditis elegans Proteins
  • GET3 protein, human
  • Insulin
  • ASNA-1 protein, C elegans
  • Arsenite Transporting ATPases
  • Cisplatin