Research Papers:

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

Sheng-Fan Wang, Meng-Shian Chen, Yueh-Ching Chou, Yune-Fang Ueng, Pen-Hui Yin, Tien-Shun Yeh and Hsin-Chen Lee _

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Oncotarget. 2016; 7:74132-74151. https://doi.org/10.18632/oncotarget.12356

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Sheng-Fan Wang1,2, Meng-Shian Chen1, Yueh-Ching Chou1,2,3, Yune-Fang Ueng1,4,5, Pen-Hui Yin6, Tien-Shun Yeh7, Hsin-Chen Lee1

1Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

2Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan

3School of Pharmacy, Taipei Medical University, Taipei, Taiwan

4National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan

5Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

6Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

7Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

Correspondence to:

Hsin-Chen Lee, email: [email protected]

Keywords: gastric cancer, mitochondrial dysfunction, cisplatin resistance, xCT, retrograde signaling

Received: June 14, 2016    Accepted: September 21, 2016    Published: September 30, 2016


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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