Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation

Redox Biol. 2021 May:41:101942. doi: 10.1016/j.redox.2021.101942. Epub 2021 Mar 13.

Abstract

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), but its clinical effects are still limited. In this study we identify Quiescin sulfhydryl oxidase 1 (QSOX1) acting as a cellular pro-oxidant, specifically in the context of sorafenib treatment of HCC. QSOX1 disrupts redox homoeostasis and sensitizes HCC cells to oxidative stress by inhibiting activation of the master antioxidant transcription factor NRF2. A negative correlation between QSOX1 and NRF2 expression was validated in tumor tissues from 151 HCC patients. Mechanistically, QSOX1 restrains EGF-induced EGFR activation by promoting ubiquitination-mediated degradation of EGFR and accelerating its intracellular endosomal trafficking, leading to suppression of NRF2 activity. Additionally, QSOX1 potentiates sorafenib-induced ferroptosis by suppressing NRF2 in vitro and in vivo. In conclusion, the data presented identify QSOX1 as a novel candidate target for sorafenib-based combination therapeutic strategies in HCC or other EGFR-dependent tumor types.

Keywords: Antioxidant; Ferroptosis; HCC; QSOX1; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular*
  • Cell Line, Tumor
  • ErbB Receptors
  • Ferroptosis*
  • Humans
  • Liver Neoplasms*
  • NF-E2-Related Factor 2
  • Oxidoreductases
  • Oxidoreductases Acting on Sulfur Group Donors
  • Sorafenib

Substances

  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Sorafenib
  • Oxidoreductases
  • Oxidoreductases Acting on Sulfur Group Donors
  • sulfhydryl oxidase
  • QSOX1 protein, human
  • EGFR protein, human
  • ErbB Receptors