Prostacyclin Inhibits Non-Small Cell Lung Cancer Growth by a Frizzled 9-Dependent Pathway That Is Blocked by Secreted Frizzled-Related Protein 1
Prostacyclin Inhibits Non-Small Cell Lung Cancer Growth by a Frizzled 9-Dependent Pathway That Is Blocked by Secreted Frizzled-Related Protein 1
复制标题
DOI：
10.1593/neo.91690
复制
发表时间：
2010-03-01
期刊：
影响因子：
4.8
通讯作者：
Winn, Robert
中科院分区：
文献类型：
--
作者：
Tennis, Meredith;Van Scoyk, Michelle;Winn, Robert
本研究的目的是评价口服活性前列环素类似物iloprost抑制人非小细胞肺癌(NSCLC)转化生长的能力，并明确iloprost的抑瘤作用机制。在一组NSCLC细胞系中，iloprost抑制转化细胞生长的能力与细胞表面前列环素受体的表达无关，而与Frizzled9(Fzd9)的存在和PPARy的激活有关。沉默FZD-9可阻断PPAR。Iloprost的激活和Fzd 9在缺乏该蛋白的细胞中的表达导致了iloprost对PPAR的激活。和抑制转化生长。有趣的是，众所周知的Wnt/Fzd信号通路的抑制剂--可溶性FrizzledR蛋白-1也阻断了iloprost和Fzd9的作用。此外，接受iloprost治疗的小鼠减少了肺癌并增加了Fzd9的表达。这些研究定义了一种新的范式，将二十烷类化合物途径与Wnt信号联系起来。此外，这些数据还表明前列环素类似物可能代表了一类新的治疗NSCLC的药物，其中非典范Wnt信号的恢复对于抑制转化细胞的生长可能具有重要意义。
The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of peroxisome proliferator-activated receptor-y (PPARy). Silencing of Fzd 9 blocked PPAR. activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPAR. and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.