Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling.
Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling.
复制标题
DOI：
10.1158/1535-7163.mct-13-0048
复制
发表时间：
2013-09
影响因子：
5.7
通讯作者：
Piazza GA
中科院分区：
文献类型：
--
作者：
Li N;Xi Y;Tinsley HN;Gurpinar E;Gary BD;Zhu B;Li Y;Chen X;Keeton AB;Abadi AH;Moyer MP;Grizzle WE;Chang WC;Clapper ML;Piazza GA
NSAID对结直肠癌和其他癌症显示出良好的抗肿瘤活性，但环氧合酶(COX)抑制的毒性限制了它们在化学预防中的长期使用。以前的研究已经得出结论，他们的肿瘤细胞生长抑制活性的基础不需要COX抑制，尽管其潜在的机制尚不清楚。本文报道了非甾体抗炎药舒林酸硫化物(SS)在抑制结肠癌细胞增殖和诱导细胞凋亡的浓度下，通过抑制cGMP-PDE活性来增加细胞内cGMP水平，并激活cGMP依赖的蛋白激酶(PKG)。SS不能激活cGMP/PKG通路，也不影响正常结肠细胞的增殖和凋亡。与结肠癌细胞相比，siRNA和PDE5特异性抑制剂他达拉非和西地那非抑制cGMP特异性PDE5同工酶也选择性地抑制高表达PDE5的结肠癌细胞的生长。SS和cGMP/PKG途径抑制结肠肿瘤细胞生长的机制可能涉及β-连环蛋白的转录抑制，从而抑制WNT/β-连环蛋白Tcf的转录活性，导致细胞周期蛋白D1和Survivin的下调。这些观察表明，通过靶向PDE5和可能的其他cGMP降解同工酶，可以开发出更安全和更有效的舒林酸衍生物用于结直肠癌的化学预防。
NSAIDs display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their tumor cell growth inhibitory activity does not required COX inhibition, although the underlying mechanism is poorly understood. Here we report that the NSAID, sulindac sulfide (SS) inhibits cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of colon tumor cells. SS did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors, tadalafil and sildenafil, also selectively inhibited the growth of colon tumor cells that expressed high levels of PDE5 compared with colonocytes. The mechanism by which SS and the cGMP/PKG pathway inhibits colon tumor cell growth appears to involve the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin TCF transcriptional activity, leading to down-regulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP degrading isozymes.