ArticleOncotarget2016
Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 90 citations in OpenAlex.
- Autophagy as a therapeutic target for cisplatin-resistant gastric cancer.Genes & diseases · 2026Review
- ANOS1 Facilitated Tumorigenesis in Gastric Cancer through the Regulation of Oxidative Phosphorylation Pathway.Journal of microbiology and biotechnology · 2026Article
- Mitochondrial Parameters influence Chemosensitivity in Gastric Cancer Cells.Journal of Cancer · 2026Article
- Exploring Emerging Therapeutic Targets in Osteosarcoma by Revisiting the Immune and Cancer-Intrinsic Hallmarks of Cancer.Cancers · 2025Review
- Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.The EMBO journal · 2025Review
- YY1-induced USP43 drives ferroptosis suppression by FASN stabilization and subsequent activation of SLC7A11 in ovarian cancer.Cell death & disease · 2025Article
- Stress response regulation of mRNA translation: Implications for antioxidant enzyme expression in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Review
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- Emerging Role of GCN1 in Disease and Homeostasis.International journal of molecular sciences · 2024Review
- Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy.Cancer reports (Hoboken, N.J.) · 2024Review
- The clinical significance of mitochondrial calcium uniporter in gastric cancer patients and its preliminary exploration of the impact on mitochondrial function and metabolism.Frontiers in oncology · 2024Article
- The role of metal ions in the occurrence, progression, drug resistance, and biological characteristics of gastric cancer.Frontiers in pharmacology · 2024Review
- Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice.Biomedicines · 2023Article
- Cellular Stress: Modulator of Regulated Cell Death.Biology · 2023Review
- Growth differentiation factor 15 induces cisplatin resistance through upregulation of xCT expression and glutathione synthesis in gastric cancer.Cancer science · 2023Article
- Role of mitochondrial alterations in human cancer progression and cancer immunity.Journal of biomedical science · 2023Review
- The Role of SLC7A11 in Cancer: Friend or Foe?Cancers · 2022Review
- GCN2: roles in tumour development and progression.Biochemical Society transactions · 2022Review
- Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells.Oncology reports · 2022Article
- Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs.Frontiers in endocrinology · 2022Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin. Clinically, the high expression of xCT was associated with a poorer prognosis for gastric cancer patients under adjuvant chemotherapy. Moreover, we found that mitochondrial dysfunction enhanced cisplatin resistance and up-regulated xCT expression, as well as intracellular glutathione (GSH). The xCT inhibitors, siRNA against xCT or BSO decreased mitochondrial dysfunction-enhanced cisplatin resistance. We further demonstrated that the upregulation of the eIF2α-ATF4 pathway contributed to mitochondrial dysfunction-induced xCT expression, and activated eIF2α kinase GCN2, but not PERK, stimulated the eIF2α-ATF4-xCT pathway in response to mitochondrial dysfunction-increased reactive oxygen species (ROS) levels. In conclusion, our results suggested that the ROS-activated GCN2-eIF2α-ATF4-xCT pathway might contribute to mitochondrial dysfunction-enhanced cisplatin resistance and could be a potential target for gastric cancer therapy.
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