Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells

作者：Xiaomin Feng, Hao Liu, Zhijie Zhang, Yixue Gu, Huisi Qiu, Zhimin He · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2017 · DOI：10.1186/s13046-017-0594-1 · 被引用次数：105 · 研究领域：S100 Proteins and Annexins、Immune Response and Inflammation、Cell death mechanisms and regulation

BACKGROUND: Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. We previously identified that Annexin A2 is significantly up-regulated in cisplatin-resistant non-small cell lung cancer (NSCLC) A549/DDP cells. However, the exact function and molecular mechanism of Annexin A2 in cisplatin resistance of NSCLCs has not been determined. METHODS: Western blot and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. Immunohistochemistry was performed to analyze the expression of Annexin A2 in NSCLC tissue samples. MTS assay, Colony formation assays, AnnexinV/PI apoptosis assay, Luciferase Reporter Assay, Chromatin-immunoprecipitation, and nude mice xenograft assay were used to visualize the function of Annexin A2 on cisplatin resistance. RESULTS: Our results demonstrated that knockdown of Annexin A2 increased cisplatin sensitivity of cisplatin-resistant A549/DDP cells both in vitro and in vivo, whereas overexpression of Annexin A2 increased cisplatin resistance of A549, H460 and H1650 cells. Moreover, we found that Annexin A2 enhanced cisplatin resistance via inhibition of cisplatin-induced cell apoptosis. Our studies showed that Annexin A2 suppressed the expression of p53 through activation of JNK/c-Jun signaling, which in turn resulted in a decrease in the expression of p53-regulated apoptotic genes p21, GADD45 and BAX, as well as p53-dependent cell apoptosis. Furthermore, we found...