Arumugam Thiruvengadam, Simeone Diane M, Van Golen Kenneth, Logsdon Craig D
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2005 Aug 1;11(15):5356-64. doi: 10.1158/1078-0432.CCR-05-0092.
In the current study, we examined the functional significance and mechanism of action of S100P in pancreatic cancer cells.
S100P levels were increased in Panc-1 cells, which do not express S100P, by transfection with an S100P cDNA and S100P levels were reduced in BxPC3 cells, which express high levels of S100P, by small interfering RNA gene silencing. Effects of these manipulations on cell proliferation, resistance to apoptotic insults, cell migration, and invasion were estimated in vitro using standard assays. The influences of S100P on tumor growth in vivo were studied using xenograft mouse models. To identify the mechanisms involved in these responses, coimmunoprecipitation studies were conducted with S100P with receptor for advanced glycation end products (RAGE) and the effects of inhibiting RAGE using an antagonistic peptide were analyzed.
S100P levels correlated with the rates of cell proliferation, survival, migration, and invasion in both cell models in vitro. In vivo, increased S100P levels increased the growth of tumors in mice with s.c.-implanted Panc-1 cells and decreased S100P levels decreased tumor growth after orthotopic implantation of BxPC-3 cells. A direct interaction between S100P and RAGE was indicated by coimmunoprecipitation of these molecules from pancreatic cancer cells. A RAGE antagonist peptide inhibited this interaction and also inhibited the biological effects of S100P on these cells in vitro.
These data suggest that S100P plays a major role in the aggressiveness of pancreatic cancer that is likely mediated by its ability to activate RAGE. Thus, interference with S100P may provide a novel approach for treatment of pancreatic cancer.
在本研究中，我们检测了S100P在胰腺癌细胞中的功能意义及作用机制。
通过用S100P cDNA转染不表达S100P的Panc-1细胞来提高其S100P水平，并用小干扰RNA基因沉默技术降低高表达S100P的BxPC3细胞中的S100P水平。使用标准检测方法在体外评估这些操作对细胞增殖、抗凋亡刺激能力、细胞迁移和侵袭的影响。使用异种移植小鼠模型研究S100P对体内肿瘤生长的影响。为了确定这些反应所涉及的机制，进行了S100P与晚期糖基化终产物受体（RAGE）的共免疫沉淀研究，并分析了使用拮抗肽抑制RAGE的效果。
在两种体外细胞模型中，S100P水平与细胞增殖、存活、迁移和侵袭率相关。在体内，提高S100P水平可增加皮下植入Panc-1细胞的小鼠肿瘤生长，而降低S100P水平可降低原位植入BxPC-3细胞后的肿瘤生长。从胰腺癌细胞中共免疫沉淀这些分子表明S100P与RAGE之间存在直接相互作用。RAGE拮抗剂肽抑制了这种相互作用，并且在体外也抑制了S100P对这些细胞的生物学效应。
这些数据表明S100P在胰腺癌的侵袭性中起主要作用，这可能是由其激活RAGE的能力介导的。因此，干扰S100P可能为胰腺癌治疗提供一种新方法。
