Gemcitabine Resistance Induced by Interaction between Alternatively Spliced Segment of Tenascin-C and Annexin A2 in Pancreatic Cancer Cells

摘要

Pancreatic cancer is the fourth leading cause of cancer-related death in the western countries and it is resist-ant to almost all cytotoxic drugs. In the current study, we explored the gemcitabine resistance induced by the in-teraction between Annexin A2 (ANXA2) and alternatively spliced segment of tenascin-C (TNfnA-D). In the pan-creatic cancer cell culture system in vitro, it was proved that exogenous recombinant TNfnA-D combined with the cell surface ANXA2 specifically and their interaction suppressed gemcitabine-induced cytotoxicity on pancre-atic cancer cells in a dose-dependent manner. Meanwhile, the TNfnA-D/ANXA2 interaction increased the phos-phorylation of phosphatidylinositol 3-kinase (PI3K), Akt, inhibitory KB (IKB) kinase α/β (IKKα/β), IKBa, and p65 nuclear factor-KB (NF-KB) significantly. Inhibition of Akt and PI3K with their specific inhibitors partially reversed the suppression of gemcitabine-induced cytotoxicity elicited by TNfnA-D/ANXA2 interaction. Activa-tion of p65 NF-KB was dependent on the phosphorylation of PI3K/Akt. The phosphorylated IKKα/β induced the phosphorylation and degradation of IkBa, the sequential phosphorylation, nuclear translocation and activation of p65 NF- KB. Pyrrolidine dithiocarbamate (PDTC) effectively blocked the activity of p65 NF-kB in response to TNfnA-D. Down-regulation of p65 NF-KB with its specific small interfering RNA (siRNA) restored the gemcitabine-induced cytotoxicity suppressed by TNfnA-D/ANXA2 interaction. For the first time, this study show that ANXA2/TNfnA-D interaction induced gemcitabine resistance via the canonical PI3K/Akt/NF-KB signaling path-ways in pancreatic cancer cells. Therefore, therapy targeting ANXA2/TNfnA-D and/or p65 NF-KB may have po-tential clinical application for patients with pancreatic cancers.