Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis
Abstract
:1. Introduction
2. Results
2.1. Salubrinal Activates ISR and Induces Cisplatin Resistance in Gastric Cancer Cells
2.2. ATF4 Plays an Essential Role in Salubrinal-Induced Cisplatin Resistance in Gastric Cancer Cells
2.3. Some of the ATF4-Regulated Genes, TRB3, HO-1, PCK2, and xCT, are Associated with Gastric Cancer Patients with Poor Prognosis after Adjuvant Chemotherapy
2.4. Up-Regulated Expression of xCT, but not of TRB3, HO-1, or PCK2, Contributes to the Salubrinal-Induced Cisplatin Resistance
2.5. Salubrinal-Induced xCT Expression is Associated with Increased Intracellular Glutathione (GSH) Biosynthesis and Decreased Cisplatin-Induced Oxidative Stress
2.6. High xCT Expression Contributes to Cisplatin Resistance of the Cisplatin-Resistant Gastric Cancer Cells
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Determination of Cell Viability
4.3. Annexin V Staining Assay
4.4. Detection of the Levels of Intracellular ROS and Mitochondrial ROS
4.5. Kaplan–Meier Plotter Analysis
4.6. Western Blot Analysis
4.7. Small Interfering RNA (siRNA)-Mediated Genetic Knockdown
4.8. Quantitative Real-Time Reverse Transcription (RT)-Polymerase Chain Reaction (q-RT PCR)
4.9. Microarray Analysis and Ingenuity Pathway Analysis (IPA)
4.10. Glutathione (GSH) Detection
4.11. Lipid Peroxidation Assay
4.12. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
5-FU | 5-Fluorouracil |
AARE | amino acid response element |
ATF4 | activating transcription factor-4 |
ATP7B | copper-transporting ATPase |
BSA | bovine serum albumin |
BSO | buthioninesulfoximine |
CO | carbon monoxide |
CTR1 | copper transporter 1 |
EDTA | ethylenediaminetetraacetic acid |
eIF2α | eukaryotic translation initiation factor 2α |
ERCC1 | excision repair cross-complementing rodent repair deficiency, complementation group 1 |
FBS | foetal bovine serum |
GAPDH | glyceraldehyde 3-phosphate dehydrogenase |
GCN2 | general control nonderepressible 2 |
GSH | glutathione |
H2O2 | hydrogen peroxide |
HO-1(HMOX1) | heme oxygenase 1 |
HRI | heme-regulated eIF2α kinase |
IPA | Ingenuity pathway analysis |
ISR | Integrated stress response |
KM | Kaplan-Meier |
MDA | Malondialdehyde |
MRP2 | multidrug resistance-associated protein 2 |
mtDNA | mitochondrial DNA |
Na3VO4 | sodium orthovanadate |
NAC | N-acetylcysteine |
NaCl | sodium chloride |
NADPH | nicotinamide adenine dinucleotide phosphate |
OS | overall survival |
P/S | penicillin/streptomycin |
PAGE | polyacrylamide gel electrophoresis |
PCK2 | phosphoenolpyruvate carboxykinase 2 |
PEPCK | phosphoenolpyruvate carboxykinase |
PERK | PKR-like endoplasmic reticulum kinase |
PFS | progression-free survival |
PKR | protein kinase R |
PMSF | phenylmethanesulfonyl fluoride |
PVDF | polyvinylidene difluoride membrane |
q-RTPCR | quantitative real-time reverse transcription-polymerase chain reaction |
ROS | reactive oxygen species |
RT | reverse transcription |
SDS | sodium dodecyl sulfate |
SRB | Sulforhodamine B |
SSA | sulfasalazine |
TCA | trichloroacetic acid |
TRB3 | tribbles-related protein 3 |
VRACs | volume-regulated anion channels |
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ATF4-Regulated Genes | Progression Free Survival | Overall Survival |
---|---|---|
High vs. Low Expression | High vs. Low Expression | |
(Hazard Ratio, HR) | (Hazard Ratio, HR) | |
TRB3 | 2.57 (1.69–3.9) | 2.55 (1.67–3.89) |
Logrank p = 5.3 × 10−6 | Logrank p = 8.9 × 10−6 | |
(n = 110 vs. 43) | (n = 110 vs. 43) | |
HO-1 | 1.55 (1.04–2.3) | 1.74 (1.15–2.63) |
Logrank p = 0.028 | Logrank p = 0.008 | |
(n = 111 vs. 42) | (n = 111 vs. 42) | |
PCK2 | 1.67 (1.15–2.42) | 1.84 (1.26–2.69) |
Logrank p = 0.0066 | Logrank p = 0.0013 | |
(n = 102 vs. 51) | (n = 43 vs. 110) | |
xCT | 1.43 (1.01–2.02) | 1.48 (1.04–2.11) |
Logrank p = 0.043 | Logrank p = 0.027 | |
(n = 71 vs. 82) | (n = 82 vs. 71) |
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Wang, S.-F.; Wung, C.-H.; Chen, M.-S.; Chen, C.-F.; Yin, P.-H.; Yeh, T.-S.; Chang, Y.-L.; Chou, Y.-C.; Hung, H.-H.; Lee, H.-C. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. Int. J. Mol. Sci. 2018, 19, 3389. https://doi.org/10.3390/ijms19113389
Wang S-F, Wung C-H, Chen M-S, Chen C-F, Yin P-H, Yeh T-S, Chang Y-L, Chou Y-C, Hung H-H, Lee H-C. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. International Journal of Molecular Sciences. 2018; 19(11):3389. https://doi.org/10.3390/ijms19113389
Chicago/Turabian StyleWang, Sheng-Fan, Chih-Hsuan Wung, Meng-Shian Chen, Chian-Feng Chen, Pen-Hui Yin, Tien-Shun Yeh, Yuh-Lih Chang, Yueh-Ching Chou, Hung-Hsu Hung, and Hsin-Chen Lee. 2018. "Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis" International Journal of Molecular Sciences 19, no. 11: 3389. https://doi.org/10.3390/ijms19113389