Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis

Autor: Hsin Chen Lee, Hung Hsu Hung, Yueh Ching Chou, Sheng Fan Wang, Meng Shian Chen, Chih Hsuan Wung, Tien Shun Yeh, Pen Hui Yin, Yuh Lih Chang, Chian Feng Chen
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Eukaryotic Initiation Factor-2
Salubrinal
lcsh:Chemistry
chemistry.chemical_compound
integrated stress response (ISR)
lcsh:QH301-705.5
Spectroscopy
chemistry.chemical_classification
Gene knockdown
Thiourea
General Medicine
Glutathione
Computer Science Applications
Up-Regulation
Gene Expression Regulation
Neoplastic
cisplatin resistance
medicine.drug
Amino Acid Transport System y+
Antineoplastic Agents
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
salubrinal
Stomach Neoplasms
Cell Line
Tumor
medicine
Integrated stress response
Humans
Physical and Theoretical Chemistry
Molecular Biology
Cisplatin
Reactive oxygen species
gastric cancer
xCT
Organic Chemistry
Activating Transcription Factor 4
Heme oxygenase
Oxidative Stress
030104 developmental biology
chemistry
lcsh:Biology (General)
lcsh:QD1-999
Cinnamates
Drug Resistance
Neoplasm
Cancer cell
Cancer research
Reactive Oxygen Species
Zdroj: International Journal of Molecular Sciences, Vol 19, Iss 11, p 3389 (2018)
International Journal of Molecular Sciences
Volume 19
Issue 11
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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