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.
Highlights
Gastric cancer is one of the most common cancers worldwide
We found that the protein expression of multidrug-resistance protein (MDR) and the function of MDR1 (p-glycoprotein, P-gp) and multidrug resistance-associated protein (MRP) were not increased in the cisplatin-resistant cells, compared to the parental cells (Supplementary Figures S1A-S1C)
We demonstrated that mitochondrial dysfunction induced by oligomycin and antimycin A might enhance cisplatin resistance in human gastric cancer cells through increased xCT expression and intracellular GSH levels, as well as through the reactive oxygen species (ROS) activation of the general control nonderepressible-2 (GCN2)-eukaryotic initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway
Summary
Gastric cancer is one of the most common cancers worldwide. The main treatment modality for gastric cancer is surgery, except for in the advanced or unresectable stages. Systemic chemotherapy based on 5-fluorouracil (5-FU) plus an anthracycline agent or cisplatin-containing combinations, is the most effective treatment modality for patients with metastatic disease [2]. Chemotherapy resistance remains an important issue in the treatment of advanced gastric cancer patients. Cancer cells usually exhibit an aberrant metabolism, and deregulated cellular energetics were recently included among the hallmarks of cancer [3]. Somatic mutations in the mitochondrial genome have been found to be frequent events in human gastric cancers, and most of these mitochondrial DNA (mtDNA) mutations can lead to mitochondrial dysfunction [5, 6]. Mitochondrial dysfunction has been suggested to contribute to cancer progression [7, 8]
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