Intracellular annexin A2 regulates NF-κB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer

Cell Death Dis. 2015 Jan 22;6(1):e1606. doi: 10.1038/cddis.2014.558.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A2 / chemistry
  • Annexin A2 / metabolism*
  • Calcium / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Genes, Neoplasm
  • Humans
  • Intracellular Space / metabolism*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Protein Subunits / metabolism*
  • Protein Transport / drug effects
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Structure-Activity Relationship
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects


  • Annexin A2
  • Protein Subunits
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Deoxycytidine
  • Calcium
  • Gemcitabine