| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Jin, Lixu Huo, Yi Zheng, Zhiguo Jiang, Xiaoyong Deng, Haiyun Chen, Yuling Lian, Qingquan Ge, Renshan Deng, Haiteng |
| Description |
Author Affiliation: Jin L ( §The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China); Huo Y ( From the School of Life Sciences, Tsinghua University, Beijing, China); Zheng Z ( ¶Zhejiang Tumor Hospital, Hangzhou, China.); Jiang X ( From the School of Life Sciences, Tsinghua University, Beijing, China); Deng H ( §The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China); Chen Y ( From the School of Life Sciences, Tsinghua University, Beijing, China); Lian Q ( §The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China); Ge R ( §The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China); Deng H ( From the School of Life Sciences, Tsinghua University, Beijing, China) |
| Abstract |
Drug resistance poses a major challenge to ovarian cancer treatment. Understanding mechanisms of drug resistance is important for finding new therapeutic targets. In the present work, a cisplatin-resistant ovarian cancer cell line A2780-DR was established with a resistance index of 6.64. The cellular accumulation of cisplatin was significantly reduced in A2780-DR cells as compared with A2780 cells consistent with the general character of drug resistance. Quantitative proteomic analysis identified 340 differentially expressed proteins between A2780 and A2780-DR cells, which involve in diverse cellular processes, including metabolic process, cellular component biogenesis, cellular processes, and stress responses. Expression levels of Ras-related proteins Rab 5C and Rab 11B in A2780-DR cells were lower than those in A2780 cells as confirmed by real-time quantitative PCR and Western blotting. The short hairpin (sh)RNA-mediated knockdown of Rab 5C in A2780 cells resulted in markedly increased resistance to cisplatin whereas overexpression of Rab 5C in A2780-DR cells increases sensitivity to cisplatin, demonstrating that Rab 5C-dependent endocytosis plays an important role in cisplatin resistance. Our results also showed that expressions of glycolytic enzymes pyruvate kinase, glucose-6-phosphate isomerase, fructose-bisphosphate aldolase, lactate dehydrogenase, and phosphoglycerate kinase 1 were down-regulated in drug resistant cells, indicating drug resistance in ovarian cancer is directly associated with a decrease in glycolysis. Furthermore, it was found that glutathione reductase were up-regulated in A2780-DR, whereas vimentin, HSP90, and Annexin A1 and A2 were down-regulated. Taken together, our results suggest that drug resistance in ovarian cancer cell line A2780 is caused by multifactorial traits, including the down-regulation of Rab 5C-dependent endocytosis of cisplatin, glycolytic enzymes, and vimentin, and up-regulation of antioxidant proteins, suggesting Rab 5C is a potential target for treatment of drug-resistant ovarian cancer. This constitutes a further step toward a comprehensive understanding of drug resistance in ovarian cancer. |
| File Format |
HTM / HTML |
| ISSN |
15359476 |
| e-ISSN |
15359484 |
| DOI |
10.1074/mcp.M113.033217 |
| Journal |
Molecular & Cellular Proteomics |
| Issue Number |
11 |
| Volume Number |
13 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology |
| Publisher Date |
2014-11-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Proteomics Cisplatin Pharmacology Endocytosis Genetics Glycolysis Ovarian Neoplasms Drug Therapy Rab5 Gtp-binding Proteins Annexin A1 Biosynthesis Annexin A2 Antineoplastic Agents Antioxidants Metabolism Biological Transport Drug Effects Cell Line, Tumor Cell Proliferation Down-regulation Drug Resistance, Neoplasm Gene Expression Profiling Glutathione Reductase Hsp90 Heat-shock Proteins Pathology Proteomics Rna Interference Rna, Small Interfering Reactive Oxygen Species Vimentin Research Support, Non-u.s. Gov't |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Medicine Analytical Chemistry Molecular Biology Biochemistry |
