Curcumin promotes KLF5 proteasome degradation through downregulating YAP/TAZ in bladder cancer cells.
Curcumin promotes KLF5 proteasome degradation through downregulating YAP/TAZ in bladder cancer cells.
复制标题
姜黄素通过下调膀胱癌细胞中的 YAP/TAZ 促进 KLF5 蛋白酶体降解
DOI：
10.3390/ijms150915173
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发表时间：
2014-08-28
影响因子：
5.6
通讯作者：
Guo P
中科院分区：
文献类型：
--
作者：
Gao Y;Shi Q;Xu S;Du C;Liang L;Wu K;Wang K;Wang X;Chang LS;He D;Guo P
KLF 5（Krüppel样因子5）通过调节细胞周期进程在正常和癌细胞增殖中起关键作用。在这项研究中，我们证明了姜黄素通过促进其蛋白酶体降解而不是通过抑制其在膀胱癌细胞中的转录来靶向KLF 5。我们还证明了基于慢病毒的KLF 5敲低抑制癌细胞生长，而Flag标记的KLF 5的过表达可以部分逆转姜黄素对细胞生长和细胞周期蛋白D1表达的影响。此外，我们发现姜黄素可以下调Hippo通路效应物雅普和TAZ的表达，这两种效应物已被报道可以保护KLF 5蛋白免于降解。事实上，通过小干扰RNA敲低雅普导致KLF 5蛋白的衰减，但不导致KLF 5 mRNA的衰减，这通过与蛋白酶体抑制剂共孵育而逆转。在裸鼠中的异种移植物测定最终证明了姜黄素对肿瘤生长和促增殖雅普/TAZ/KLF 5/细胞周期蛋白D1轴的有效抑制作用。因此，我们的数据表明，姜黄素通过靶向膀胱癌细胞中的雅普/TAZ促进KLF 5蛋白酶体依赖性降解，并且还表明姜黄素在膀胱癌治疗中的治疗潜力。
KLF5 (Krüppel-like factor 5) plays critical roles in normal and cancer cell proliferation through modulating cell cycle progression. In this study, we demonstrated that curcumin targeted KLF5 by promoting its proteasome degradation, but not by inhibiting its transcription in bladder cancer cells. We also demonstrated that lentivirus-based knockdown of KLF5 inhibited cancer cell growth, while over-expression of a Flag-tagged KLF5 could partially reverse the effects of curcumin on cell growth and cyclin D1 expression. Furthermore, we found that curcumin could down-regulate the expression of Hippo pathway effectors, YAP and TAZ, which have been reported to protect KLF5 protein from degradation. Indeed, knockdown of YAP by small interfering RNA caused the attenuation of KLF5 protein, but not KLF5 mRNA, which was reversed by co-incubation with proteasome inhibitor. A xenograft assay in nude mice finally proved the potent inhibitory effects of curcumin on tumor growth and the pro-proliferative YAP/TAZ/KLF5/cyclin D1 axis. Thus, our data indicates that curcumin promotes KLF5 proteasome-dependent degradation through targeting YAP/TAZ in bladder cancer cells and also suggests the therapeutic potential of curcumin in the treatment of bladder cancer.
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影响因子：
11.2
作者：
Chadalapaka G;Jutooru I;Chintharlapalli S;Papineni S;Smith R 3rd;Li X;Safe S
通讯作者：
Safe S
影响因子：
4.8
作者：
Chen, CS;Sun, XD;Dong, JT
通讯作者：
Dong, JT
影响因子：
4.8
作者：
Guo, Peng;Dong, Xue-Yuan;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
5.8
作者：
Aggarwal, Bharat B.;Banerjee, Sanjeev;Sethi, Gautam
通讯作者：
Sethi, Gautam
影响因子：
4.3
作者：
Dong, Shao-zhuang;Zhao, Shui-ping;Nie, Sai
通讯作者：
Nie, Sai