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

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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-kappa B signaling pathways. ANXA2 bound to the p50 subunit of NF-kappa B in a calcium-independent manner, and the ANXA2-p50 complex translocated into the nucleus. Furthermore, ANXA2 increased the transcriptional activity of NF-kappa B in both the resting and activated states and upregulated the transcription of several target genes downstream of NF-kappa B, 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-kappa B 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-alpha or gemcitabine. Based on these results, we suggest that ANXA2 mediates resistance to gemcitabine by directly increasing the activity of NF-kappa B. 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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2015-01
Language
English
Article Type
Article
Keywords

DRUG-RESISTANCE; UP-REGULATION; IN-VIVO; CELLS; ACTIVATION; GROWTH; DIFFERENTIATION; PROGASTRIN; INTERLEUKIN-6; PROGRESSION

Citation

CELL DEATH & DISEASE, v.6

ISSN
2041-4889
DOI
10.1038/cddis.2014.558
URI
http://hdl.handle.net/10203/195562
Appears in Collection
BS-Journal Papers(저널논문)
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