title: JWA reverses cisplatin resistance via the CK2-XRCC1 pathway in human gastric cancer cells.
abstract: Gastric cancer is the third most common malignancy in China, with a median 5-year survival of only 20%. Cisplatin has been used in first-line cancer treatment for several types of cancer including gastric cancer. However, patients are often primary resistant or develop acquired resistance resulting in relapse of the cancer and reduced survival. Recently, we demonstrated that the reduced expression of base excision repair protein XRCC1 and its upstream regulator JWA in gastric cancerous tissues correlated with a significant survival benefit of adjuvant first-line platinum-based chemotherapy as well as XRCC1 playing an important role in the DNA repair of cisplatin-resistant gastric cancer cells. In the present study, we demonstrated the role of JWA in cisplatin-induced DNA lesions and aquired cisplatin resistance in five cell-culture models: gastric epithelial cells GES-1, cisplatin-sensitive gastric cancer cell lines BGC823 and SGC7901, and the cisplatin-resistant gastric cancer cell lines BGC823/DDP and SGC7901/DDP. Our results indicated that JWA is required for DNA repair following cisplatin-induced double-strand breaks (DSBs) via XRCC1 in normal gastric epithelial cells. However, in gastric cancer cells, JWA enhanced cisplatin-induced cell death through regulation of DNA damage-induced apoptosis. The protein expression of JWA was significantly decreased in cisplatin-resistant cells and contributed to cisplatin resistance. Interestingly, as JWA upregulated XRCC1 expression in normal cells, JWA downregulated XRCC1 expression through promoting the degradation of XRCC1 in cisplatin-resistant gastric cancer cells. Furthermore, the negative regulation of JWA to XRCC1 was blocked due to the mutation of 518S/519T/523T residues of XRCC1, and indicating that the CK2 activated 518S/519T/523T phosphorylation is a key point in the regulation of JWA to XRCC1. In conclusion, we report for the first time that JWA regulated cisplatin-induced DNA damage and apoptosis through the CK2-P-XRCC1-XRCC1 pathway, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.
authors.affiliation: 1] Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China [2] Laboratory of Cancer Biology, Biomedical Research Center, Sir Runrun Shaw Hospital, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China.
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China.
authors.forename: A
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway and Cancer Clinic, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger 7600, Norway.
authors.forename: O D
authors.initials: OD
authors.lastname: Røe
authors.affiliation: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 Coulter Street, Suite 1117, Amarillo, TX 79106, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 Coulter Street, Suite 1116, Amarillo, TX 79106, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: 1] Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China [2] Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, 818 East Tianyuan Road, Nanjing 211166, People's Republic of China [3] Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, 818 East Tianyuan Road, Nanjing, 211166 People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D047390:Casein Kinase II / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D010766:Phosphorylation; D015398:Signal Transduction; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: C484566:ARL6IP5 protein, human; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D047390:Casein Kinase II; D002945:Cisplatin