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 MiaPaca2 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.

S100A11 functions as novel oncogene in glioblastoma via S100A11/ANXA2/NF‐κB positive feedback loop

“…NF‐κB is closely associated with the progression of numerous cancers . ANXA2 is closely associated with NF‐kB pathway . Here, we detected whether the NF‐κB signalling was involved in S100A11/ANXA2 signalling in GBM.…”

“…Annexin A2 (ANXA2), belongs to annexin family, is a calcium‐dependent phospholipid‐binding protein. ANXA2 is overexpressed in numerous tumours, including glioma . Aberrantly, expression of ANXA2 plays important roles in tumour development by regulating cell proliferation, apoptosis, invasion and metastasis …”

“…ANXA2 is overexpressed in numerous tumours, including glioma. [11][12][13][14] Aberrantly, expression of ANXA2 plays important roles in tumour development by regulating cell proliferation, apoptosis, invasion and metastasis. 15 In this study, we investigated the roles of S100A11 in GBM tumorigenicity, particularly GBM cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion and neurosphere formation via silencing or overexpression in GBM.…”

Set7/9, a methyltransferase, regulates the thermogenic program during brown adipocyte differentiation through the modulation of p53 acetylation

“…Flag-tagged mouse Set7/9 was inserted into the pRetroX-IRES-ZsGreen1 vector (Clontech) as described previously (Jung et al, 2015;Kim et al, 2013a). The Set7/9 mutant was constructed by performing site-directed mutagenesis using a QuikChange mutagenesis kit (Stratagene) according to the manufacturer's instructions.…”

“…All animals were handled in accordance with The Guidelines of Animal Care recommended by the Korea Research Institute of Bioscience and Biotechnology (KRIBB). For analysis of Sirt1 and Set7/9 interaction, we performed the immunoprecipitation assay as previously described (Jung et al, 2015). In brief, total protein lysates from cells transfected with a control vector or vector encoding FLAG-Set7/9 were resuspended with lysis buffer (20 mM Tris, 137 mM NaCl, 1 mM EDTA, 10% glycerol, and 1% NP-40) containing protease inhibitors, and were incubated at 4 C overnight on a tube rotator with FLAG antibodyconjugated protein A/G agarose beads.…”