title: TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer.
abstract: Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.
authors: 1] Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Nanjing, People's Republic of China [2] Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing, People's Republic of China [3] School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
authors: W
authors: W
authors: Xu
authors: 1] Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Nanjing, People's Republic of China [2] Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing, People's Republic of China [3] School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
authors: S
authors: S
authors: Wang
authors: 1] Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Nanjing, People's Republic of China [2] Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing, People's Republic of China [3] School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
authors: Q
authors: Q
authors: Chen
authors: Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, People's Republic of China.
authors: Y
authors: Y
authors: Zhang
authors: Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, People's Republic of China.
authors: P
authors: P
authors: Ni
authors: Department of Oncology, Nantong Cancer Hospital, Jiangsu Province, People's Republic of China.
authors: X
authors: X
authors: Wu
authors: Department of Oncology, Nantong Cancer Hospital, Jiangsu Province, People's Republic of China.
authors: J
authors: J
authors: Zhang
authors: Department of Oncology, Nantong Cancer Hospital, Jiangsu Province, People's Republic of China.
authors: F
authors: F
authors: Qiang
authors: 1] Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Nanjing, People's Republic of China [2] Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing, People's Republic of China [3] School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
authors: A
authors: A
authors: Li
authors: 1] Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway [2] Cancer Clinic, LevangerHospital, Nord-Trøndelag Health Trust, Levanger, Norway.
authors: O D
authors: OD
authors: Røe
authors: Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, People's Republic of China.
authors: S
authors: S
authors: Xu
authors: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors: M
authors: M
authors: Wang
authors: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors: R
authors: R
authors: Zhang
authors: 1] Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Nanjing, People's Republic of China [2] Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing, People's Republic of China [3] School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
authors: J
authors: J
authors: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C504766:TXNL1 protein, human; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D013879:Thioredoxins; D000077146:Irinotecan; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin; D002166:Camptothecin