Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans

Sci Rep. 2021 Apr 21;11(1):8678. doi: 10.1038/s41598-021-88085-y.

Abstract

Cisplatin is a frontline cancer therapeutic, but intrinsic or acquired resistance is common. We previously showed that cisplatin sensitivity can be achieved by inactivation of ASNA-1/TRC40 in mammalian cancer cells and in Caenorhabditis elegans. ASNA-1 has two more conserved functions: in promoting tail-anchored protein (TAP) targeting to the endoplasmic reticulum membrane and in promoting insulin secretion. However, the relation between its different functions has remained unknown. Here, we show that ASNA-1 exists in two redox states that promote TAP-targeting and insulin secretion separately. The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants in wrb-1, which we identify as the C. elegans homolog of WRB, the ASNA1/TRC40 receptor. Finally, we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin induced ROS drives ASNA-1 into the oxidized form, and selectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmic reticulum. Our work suggests that ASNA-1 acts as a redox-sensitive target for cisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environment should be explored as possible means to combat cisplatin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenite Transporting ATPases / metabolism*
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans Proteins / metabolism*
  • Cisplatin / pharmacology*
  • Drug Resistance
  • Endoplasmic Reticulum / metabolism
  • Insulin / metabolism*
  • Oxidation-Reduction
  • Reactive Oxygen Species / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Insulin
  • Reactive Oxygen Species
  • ASNA-1 protein, C elegans
  • Arsenite Transporting ATPases
  • Cisplatin