期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 19, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/ijms19113389
关键词
gastric cancer; integrated stress response (ISR); cisplatin resistance; salubrinal; xCT
资金
- Taipei Veterans General Hospital, Taipei, Taiwan [V105A-018, V106A-020]
- Cheng Hsin General Hospital [CY10605, CY10707]
- Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan
- Ministry of Science and Technology, Taiwan [MOST 106-2320-B-010-032, MOST 107-2320-B-010-044]
- SPROUT Project-Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B) of National Chiao Tung University, from the Ministry of Education, Taiwan
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 2 alpha (eIF2 alpha)- 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 eIF2 alpha 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.
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