文章基本信息

标题：Gemcitabine Resistance Induced by Interaction between Alternatively Spliced Segment of Tenascin-C and Annexin A2 in Pancreatic Cancer Cells
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作者：Xiao-Guang Gong ; Yun-Fu Lv ; Xin-Qiu Li 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2010
卷号：33
期号：8
页码：1261-1267
DOI：10.1248/bpb.33.1261
出版社：The Pharmaceutical Society of Japan
摘要：Pancreatic cancer is the fourth leading cause of cancer-related death in the western countries and it is resistant to almost all cytotoxic drugs. In the current study, we explored the gemcitabine resistance induced by the interaction between Annexin A2 (ANXA2) and alternatively spliced segment of tenascin-C (TNfnA-D). In the pancreatic 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 pancreatic cancer cells in a dose-dependent manner. Meanwhile, the TNfnA-D/ANXA2 interaction increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, inhibitory κB (IκB) kinase α/β (IKKα/β), IκBα, and p65 nuclear factor-κB (NF-κB) significantly. Inhibition of Akt and PI3K with their specific inhibitors partially reversed the suppression of gemcitabine-induced cytotoxicity elicited by TNfnA-D/ANXA2 interaction. Activation of p65 NF-κB was dependent on the phosphorylation of PI3K/Akt. The phosphorylated IKKα/β induced the phosphorylation and degradation of IκBα, the sequential phosphorylation, nuclear translocation and activation of p65 NF-κB. Pyrrolidine dithiocarbamate (PDTC) effectively blocked the activity of p65 NF-κB in response to TNfnA-D. Down-regulation of p65 NF-κB 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-κB signaling pathways in pancreatic cancer cells. Therefore, therapy targeting ANXA2/TNfnA-D and/or p65 NF-κB may have potential clinical application for patients with pancreatic cancers.
关键词：gemcitabine;pancreatic cancer;Annexin A2;tenascin-C;drug resistance