Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway.

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.

• Authors: Sheng-Fan Wang, Meng-Shian Chen, Yueh-Ching Chou, Yune-Fang Ueng, Pen-Hui Yin, Tien-Shun Yeh, Hsin-Chen Lee
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 45 Pg. 74132-74151 (Nov 08 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27708226 (Publication Type: Journal Article)

Chemical References

• ATF4 protein, human
• Amino Acid Transport System y+
• Antineoplastic Agents
• Reactive Oxygen Species
• SLC7A11 protein, human
• Activating Transcription Factor 4
• EIF2AK4 protein, human
• Protein Serine-Threonine Kinases
• Cisplatin

Topics

• Activating Transcription Factor 4 (metabolism)
• Amino Acid Transport System y+ (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• HEK293 Cells
• Humans
• Mitochondria (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Transfection