title: Intracellular annexin A2 regulates NF-κB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer.
abstract: Annexin A2 (ANXA2) expression is highly upregulated in many types of cancer. Although cell surface localization of ANXA2 has been reported to have a critical role in the progression and metastasis of a variety of tumors, including pancreatic cancer, the biological role of intracellular ANXA2 is not fully understood. Herein the role of intracellular ANXA2 was investigated in a pancreatic cancer cell line. We first determined whether ANXA2 is involved in NF-κB signaling pathways. ANXA2 bound to the p50 subunit of NF-κB in a calcium-independent manner, and the ANXA2-p50 complex translocated into the nucleus. Furthermore, ANXA2 increased the transcriptional activity of NF-κB in both the resting and activated states and upregulated the transcription of several target genes downstream of NF-κB, including that encoding interleukin (IL)-6, which contributes to anti-apoptotic signaling. In Mia-Paca2 cells, we determined the effects of wild-type ANXA2 and an ANXA2 mutant, Y23A, which suppresses the cell surface localization, on upregulation of NF-κB transcriptional activity and secretion of IL-6. Both wild-type and Y23A ANXA2 induced anti-apoptotic effects in response to treatment with tumor necrosis factor-α or gemcitabine. Based on these results, we suggest that ANXA2 mediates resistance to gemcitabine by directly increasing the activity of NF-κB. Collectively, these data may provide additional information about the biological role of ANXA2 in pancreatic cancer and suggest that ANXA2 is a potential biomarker for the drug resistance phenotype and a candidate therapeutic target for the treatment of pancreatic cancer.
authors.affiliation: 1] Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Republic of Korea [2] Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Jung
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: W K
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: K-J
authors.initials: KJ
authors.lastname: Oh
authors.affiliation: Department of Pathology, College of Medicine, Chungnam National University, Daejeon, 301-721, Republic of Korea.
authors.forename: J-M
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chungnam National University, Daejeon, 301-721, Republic of Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: B S
authors.initials: BS
authors.lastname: Han
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: D S
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Republic of Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Seo
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: S C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: S G
authors.initials: SG
authors.lastname: Park
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Bae
mesh_terms: D017306:Annexin A2 / Q000737:chemistry / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D052138:Genes, Neoplasm; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D017306:Annexin A2; D021122:Protein Subunits; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D002118:Calcium; D000093542:Gemcitabine