1. Academic Validation
  2. Ferroptosis signaling promotes the release of misfolded proteins via exosomes to rescue ER stress in hepatocellular carcinoma

Ferroptosis signaling promotes the release of misfolded proteins via exosomes to rescue ER stress in hepatocellular carcinoma

  • Free Radic Biol Med. 2023 Mar 28;S0891-5849(23)00133-8. doi: 10.1016/j.freeradbiomed.2023.03.027.
Jian Yang 1 Huanji Xu 2 Wanlong Wu 3 Huixi Huang 2 Chenliang Zhang 2 Weiping Tang 2 Qinlin Tang 2 Feng Bi 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China; West China Second Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
  • 2 Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
  • 3 West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
  • 4 Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China. Electronic address: xiaodaishu98@163.com.
Abstract

Dysfunction of the ubiquitin‒proteasome system can induce sustained endoplasmic reticulum stress (ERS) and subsequent cell death. However, malignant cells have evolved multiple mechanisms to evade sustained ERS. Therefore, identification of the mechanisms through which tumor cells develop resistance to ERS is important for the therapeutic exploitation of these cells for drug-resistant tumors. Herein, we found that Proteasome inhibitors could induce ERS, activate Ferroptosis signaling, and thereby induce the adaptive tolerance of tumor cells to ERS. Mechanistically, the activation of Ferroptosis signaling was found to promote the formation and secretion of exosomes containing misfolded and unfolded proteins, which resulted in rescuing ERS and promoting tumor cell survival. The inhibition of Ferroptosis signaling synergized with bortezomib, a clinically used Proteasome Inhibitor, to suppress the viability of hepatocellular carcinoma cells in vitro and in vivo. The present findings reveal that ERS resistance can be driven by an ERS-ferroptosis signaling-exosome pathway and have important clinical implications for intracellular signaling, ER homeostasis and drug-resistant Cancer therapy.

Keywords

Arachidonic acid; Bortezomib; Endoplasmic reticulum stress; Exosomes; Ferroptosis; Hepatocellular carcinoma.

Figures
Products