Activated integrated stress response induced by salubrinal promotes cisplatin resistance in human gastric cancer cells via enhanced xct expression and glutathione biosynthesis

Sheng Fan Wang, Chih Hsuan Wung, Meng Shian Chen, Chian Feng Chen, Pen Hui Yin, Tien Shun Yeh, Yuh Lih Chang, Yueh Ching Chou, Hung Hsu Hung*, Hsin Chen Lee

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)—eukaryotic translation initiation factor 2α (eIF2α)—activating transcription factor-4 (ATF4) pathway-mediated cisplatin resistance of human gastric cancer cells. However, whether or how ISR activation per se could enhance chemoresistance remains unclear. In this study, we used eIF2α phosphatase inhibitor salubrinal to activate the ISR pathway and found that salubrinal reduced susceptibility to cisplatin. Moreover, salubrinal up-regulated ATF4-modulated gene expression, and knockdown of ATF4 attenuated salubrinal-induced drug resistance, suggesting that ATF4-modulated genes contribute to the process. The ATF4-modulated genes, xCT (a cystine/glutamate anti-transporter), tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), and phosphoenolpyruvate carboxykinase 2 (PCK2), were associated with a poorer prognosis for gastric cancer patients. By silencing individual genes, we found that xCT, but not TRB3, HO-1, or PCK2, is responsible for salubrinal-induced cisplatin resistance. In addition, salubrinal increased intracellular glutathione (GSH) and decreased cisplatin-induced lipid peroxidation. Salubrinal-induced cisplatin resistance was attenuated by inhibition of xCT and GSH biosynthesis. In conclusion, our results suggest that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells.

Original languageEnglish
Article number3389
JournalInternational Journal Of Molecular Sciences
Volume19
Issue number11
DOIs
StatePublished - Nov 2018

Keywords

  • Cisplatin resistance
  • Gastric cancer
  • Integrated stress response (ISR)
  • Salubrinal
  • XCT

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