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.
Highlights
Expression of Annexin A2 (ANXA2) is upregulated in pancreatic cancer cell lines and primary pancreatic tumors.[6,7,8] Akt/mTOR signaling is responsible, at least in part, for the upregulation of ANXA2 observed in recurrent pancreatic cancer following adjuvant therapy with gemcitabine
ANXA2 interacts with the p50 subunit of NF-κB in a calcium-independent manner
We examined whether the biological role of intracellular ANXA2 in the regulation of anti-apoptotic gene expression, via its interaction with p50, co-translocation into the nucleus, and upregulation of the transcriptional activity of the p50 subunit, is related to the drug resistance phenotype in pancreatic cancer cells
Summary
Expression of ANXA2 is upregulated in pancreatic cancer cell lines and primary pancreatic tumors.[6,7,8] Akt/mTOR signaling is responsible, at least in part, for the upregulation of ANXA2 observed in recurrent pancreatic cancer following adjuvant therapy with gemcitabine. It was suggested that ANXA2 may be a predictive marker for recurrence in this setting.[7,9] We have recently demonstrated that ANXA4 regulates the transcriptional activity of NF-κB by binding to the p50 subunit of NF-κB in a calcium-dependent manner.[10] NF-κB is a transcription factor that acts as an essential regulator of innate and adaptive immune responses, inflammation, apoptosis, cell survival, proliferation, and angiogenesis.[11,12] The five NF-κB family members, such as NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and c-Rel, have been identified. We demonstrate for the first time that ANXA2 upregulates the transcriptional activity of NF-κB by binding to and facilitating nuclear translocation of the p50 subunit of NF-κB. Overexpression of ANXA2 is linked to gemcitabine resistance in pancreatic carcinoma through NF-κB-dependent expression of several antiapoptotic genes
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