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.
Highlights
The incidence of gastric cancer has declined and reached a plateau, and gastric cancer mortality is declining due to improvements in surgical and systemic treatments as well as screening, early detection, and treatment strategies for Helicobacter pylori infection, gastric cancer is still a considerable global health burden [1]
We found that salubrinal significantly decreases cellular sensitivity to cisplatin (Figure 1C) and decreases the cisplatin-induced annexin V-positive population (Figure 1D). These results suggest that salubrinal activates integrated stress response (ISR) and induces cisplatin resistance in gastric cancer cells
To confirm that the up-regulation of these four genes is activating transcription factor-4 (ATF4)-dependent, we used Small Interfering RNA (siRNA) to knock down ATF4 and found that the salubrinal-up-regulated expression of these four proteins is significantly attenuated (Figure 3B). These results indicate that the salubrinal-up-regulated expression of tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), phosphoenolpyruvate carboxykinase 2 (PCK2), and xCT is ATF4-dependent. These results suggest that TRB3, HO-1, PCK2, and xCT have the potential to be involved in the ISR-enhanced cisplatin resistance
Summary
The incidence of gastric cancer has declined and reached a plateau, and gastric cancer mortality is declining due to improvements in surgical and systemic treatments as well as screening, early detection, and treatment strategies for Helicobacter pylori infection, gastric cancer is still a considerable global health burden [1]. Surgery is the major treatment for patients with local gastric cancer. For patients with metastatic disease, systemic chemotherapy is the most effective treatment modality and could adequately palliate the symptoms of gastric cancer [2]. The 5-Fluorouracil (5-FU) derivative and platinum medications are often prescribed for systemic chemotherapy to treat gastric cancer [3,4,5]. Despite the acceptable efficacy of systemic combination chemotherapy treatment, some gastric cancer patients relapsed after several months of treatment [6]. Chemotherapy resistance-mediated cancer progression is still an important issue for the treatment of gastric cancer patients
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