Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.
Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.
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DOI：
10.18632/oncotarget.4741
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发表时间：
2015-09-29
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影响因子：
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通讯作者：
Piazza GA
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作者：
Li N;Chen X;Zhu B;Ramírez-Alcántara V;Canzoneri JC;Lee K;Sigler S;Gary B;Li Y;Zhang W;Moyer MP;Salter EA;Wierzbicki A;Keeton AB;Piazza GA
先前的研究表明，抗炎药舒林酸通过一种不依赖于COX的机制抑制肿瘤发生，包括抑制cGMP PDE。在这里，我们报道了cGMP PDE同工酶PDE5和10在结肠肿瘤细胞中与正常结肠细胞相比升高，并且抑制剂和sirna可以选择性地抑制结肠肿瘤细胞的生长。与单独使用同工酶相比，联合使用抑制剂或双重敲除抑制肿瘤细胞生长的程度更大。一种新的舒林酸衍生物ADT-094缺乏COX-1/ 2抑制活性，但对PDE5和pde10的抑制能力有所提高。ADT-094通过激活cGMP/PKG信号，抑制结肠癌细胞增殖，诱导细胞凋亡，其抑制结肠癌细胞生长的效力是舒林酸的500倍。通过ADT-094、PDE同工酶选择性抑制剂或siRNA敲低联合抑制PDE5和10也会抑制β-catenin、TCF转录活性以及下游靶点cyclin D1和survivin的水平。这些结果表明，PDE5和pde10的双重抑制为开发强效和选择性抗癌药物提供了新的策略。
Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs.